Polymorphisms of the OCTN1 and OCTN2 cation transporters associated with inflammatory bowel disorders

ABSTRACT

The invention provides a method for diagnosing Inflammatory Bowel Diseases, using genetic markers that are implicated in severe, early-onset Crohn&#39;s Disease (CD). The invention also provides coding sequence mutations in the OCTN1 gene that significantly reduces its ability to transport the organic cation carnitine. The invention further provides mutations in the promoter region of OCTN2 (that downregulates both basal transcription and transcription induced either by heat shock or arachidonic acid. This transcription difference is apparently due to the disruption of a binding site for heat shock transcription factor 1 (HSF1). A haplotype of two mutations is found in Crohn&#39;s Disease (CD) patients. Together, these mutations reduce cellular ability to respond to metabolic stress in inflamed tissue and may further be involved in the clearance of toxic substances from cells. The invention provides for the identification and use of these polynucleotides and encoded polypeptide sequences as targets for the development of therapeutic compounds intended to be useful in the treatment of Inflammatory Bowel Diseases and inflammation generally.

CLAIM OF PRIORITY

[0001] This patent claims priority to U.S. provisional patent applications Ser. Nos. 60/343,338, filed Dec. 21, 2001; 60/362,700, filed Mar. 8, 2002; 60/362,717, filed Mar. 8, 2002; and 60/427,529, filed Nov. 19, 2002.

FIELD OF THE INVENTION

[0002] This invention relates generally to the analysis of biological material. In particular, the invention relates to diagnostic analyses for markers that are associated with inflammatory disorders of the gastrointestinal tract, and to their uses for the development of novel therapeutic treatments for inflammatory disorders.

BACKGROUND OF THE INVENTION

[0003] Crohn's Disease (CD) is an idiopathic condition characterized by chronic, relapsing intestinal inflammation, with most patients developing symptoms in early adulthood. It is a subset of the Inflammatory Bowel Diseases (IBD) which include Crohn's Disease, indeterminate colitis (IC) and Ulcerative Colitis (UC).

[0004] These conditions affect a relatively large portion of the population, with varying estimates of prevalence around 300,000 in North America. Inflammatory Bowel Diseases have a high economic impact, with costs running into the billions of dollars.

[0005] Genetic studies have indicated the presence of several loci predisposing to Inflammatory Bowel Diseases, the most widely replicated of which are on chromosomes 16 (caused by mutations in the NOD2/CARD15 gene), 12, 6 and 14. A locus at chromosome 5q31, termed IBD5, which predisposes to early-onset Crohn's Disease (with age of onset 16 years or earlier) has been described by Rioux J D et al., Nature Genet. 29, 223-228 (2001). This locus is marked by a risk haplotype of 11 Single Nucleotide Polymorphisms (SNPs) over a region of approximately 250-kb. The region contains multiple candidate genes including the genes for organic cation transporters (OCTN1/SLC22A4 and OCTN2/SLC22A5), the gene for a LIM-domain-containing protein (RIL/PDLIM3), the gene for the α2 subunit of proline-4-hydroxylase (P4HA2) and a gene of unknown function (NCBI UniGene identifier Hs.70932). Because of extensive linkage disequilibrium (LD) in this region, it had not previously been possible to further refine the SNP map and unambiguously identify a single susceptibility gene.

[0006] Thus, there is a continuing need in the medical arts for genetic markers of Crohn's Disease and guidance for the use of such markers.

SUMMARY OF THE INVENTION

[0007] The invention provides a method for diagnosing Inflammatory Bowel Diseases, using genetic markers that are implicated in severe, early-onset Crohn's Disease (CD). The invention also provides coding sequence mutations in the OCTN1 gene (the human OCTN1 gene, also known as “Homo sapiens solute carrier family 22 (organic cation transporter), member 4 (SLC22A4)”) that significantly reduces its ability to transport the organic cation carnitine. The invention further provides mutations in the promoter region of OCTN2 (the human OCTN2 gene, also known as “Homo sapiens solute carrier family 22 (organic cation transporter), member 5 (SLC22A5)”) that downregulates both basal transcription and transcription induced either by heat shock or arachidonic acid. This transcription difference is apparently due to the disruption of a binding site for heat shock transcription factor 1 (HSF1). The invention further provides a haplotype of these two mutations in combination. The two genes, OCTN1 and OCTN2, show significant downregulation in inflamed Crohn's Disease tissue.

[0008] The identified OCTN1 and OCTN2 sequence variations have diagnostic and pharmacogenetic utility and reveal a disease-related molecular pathway that can be targeted for therapeutic intervention. The OCTN1 and OCTN2 genes are differentially expressed in inflamed and non-inflamed colon tissue from CD patients. Both genes contain disease-associated DNA sequence variations (polymorphisms). The identified polynucleotide polymorphisms are thus the basis for a diagnostic and prognostic test describing susceptibility to Inflammatory Bowel Diseases in certain individuals. The invention also provides for the identification and use of these polynucleotides and encoded polypeptide sequences as targets for the development of therapeutic compounds intended to be useful in the treatment of Inflammatory Bowel Diseases and inflammation generally.

[0009] The invention also provides a model for Crohn's Disease, wherein the combined effect of these two mutations results in overall poor carnitine transport, particularly in response to inflammation. As carnitine is a cofactor required for the uptake of long-chain fatty acids into the mitochondria for subsequent β-oxidation, the effect of this mutation haplotype leads to metabolic stress, which contributes to inflammatory damage to gastrointestinal tract tissue in Crohn's Disease patients. In addition, the invention provides evidence of an association between the OCTN1 and OCTN2 genes and generalized inflammatory responses. This model provides the basis for the therapeutic treatment of Inflammatory Bowel Diseases. The invention also provides a model for Crohn's Disease, wherein the effect of mutations in OCTN1 results in overall poor efflux of molecules from the cell. These molecules could include toxic metabolites, bacterial endotoxins, xenobiotics, pharmaceutical compounds used to treat inflammation, or free radical species.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a set of Northern blots showing a differential expression of OCTN1 and OCTN2 in inflamed tissue. Northern blots probed with OCTN1, OCTN2 or GAPDH are shown at the left of FIG. 1. Bar graphs of the relative optical density (normalized to GAPDH) corresponding to OCTN1 expression (right side, above) or OCTN2 expression (right side, below) are shown at the right, with value±SEM labeled on the bar. p-values of significance are shown above the bar corresponding to inflamed tissue. HC: normal human colon. J: Jurkat T-cell leukemia cells. UC-N: non-inflamed tissue from Ulcerative Colitis patient. UC-I: inflamed tissue from Ulcerative Colitis patient. CD-N: non-inflamed tissue from Crohn's Disease patient. CD-I: inflamed tissue from Crohn's Disease patient.

[0011]FIG. 2 is a set of bar graphs showing that a G-207C mutation in the heat shock enhancer (HSE) of the promoter region of OCTN2 gene results in downregulation of luciferase reporter gene under heat shock and arachidonate treatment. HeLa cells transfected with constructs containing the luciferase reporter gene fused to the 2.7-kb region of OCTN2 promoter with wild-type (G-207) or mutant (G-207C) alleles. Relative luminescence of transfected OCTN2 promoter constructs was measured in untreated control cells (37° C.), cells exposed to a standard heat shock (42° C.) and to 20 μM arachidonic acid (arachidonate). Values are means of three independent experiments. Error bars are the SEM. G: nonrisk allele at position −207 of the OCTN2 promoter; C: risk allele.

[0012]FIG. 3 is a set of bar graphs showing the carnitine transport by human HeLa (FIG. 3A) and human OCTN2 deficient cell line (FIG. 3B), transfected with OCTN1 cDNA with L503 or the mutant L1503F allele. Cells transfected with pcDNA3 vector alone served as a control. Uptake of [³H]-carnitine (20 nM) was measured at pH 7.5 in a media containing NaCl. Carnitine uptake was calculated as cpm/mg protein/min, values were corrected for transfection efficiency and the uptake was normalized with respect to the value of the mock transfected cells. Points are means±SE of three (FIG. 3A) to six (FIG. 3B) determinations in three (FIG. 3A) or two (FIG. 3B) independent experiments.

[0013]FIG. 4 is a set of bar graphs showing TEA efflux by the mutant 503F and wild-type 503L variants of OCTN1. Intracellular retention of radiolabeled TEA is shown as a percentage of the maximally retained amount at time zero. OCTN1-F: L503F variant of OCTN1. OCTN1-L: wild-type 503L variant of OCTN1. Points are means±SE of three determinations.

[0014]FIG. 5 is a set of bar graphs showing the luciferase activities of the pRL-null vector containing 2.7 kb OCTN2 promoter region.

[0015]FIG. 6 shows the genomic DNA sequence including the OCTN2 gene. Locations of exons are highlighted in yellow. Locations of primer sequences used are highlighted in green (note that the O2X1F primer is located within exon 1, and that O2X1R is the reverse complement of the sequence as shown). Start and stop codons of the coding sequence are highlighted in red. Mutations within the 5′ region of the gene are highlighted and are shown with standard DNA nomenclature for polymorphic bases, i.e. “K” meaning G or T, “Y” meaning C or T, “R” meaning A or G, and “S” meaning C or G.

[0016]FIG. 7 shows in graphical form the expression level of the OCTN2 gene, expressed as relative optical density (“ROD”) of autoradiographic signal from the OCTN2 gene as compared to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Blue bars represent expression level from RNA extracted from surgically removed non-inflamed GI tract tissue, and red bars represent expression level from RNA extracted from surgically removed inflamed GI tract tissue. Individual RNA samples are identified below the bars with a unique identifier number (e.g. 7403) and patient's diagnosis (“UC” for Ulcerative Colitis, “CD” for Crohn's Disease). Control unaffected samples are labeled as “HC male” and “HC female” and are from individuals without Inflammatory Bowel Disease. FIGS. 7A-D each represent data from a single “Northern blot” (i.e. DNA:RNA hybridization experiment); for each blot, individual sample results are presented in the top panel and averaged results for inflamed and non-inflamed samples are presented in the bottom panel. In the bottom panel, each bar is labeled with its mean value and standard error of the mean (SEM). Statistical p-values are also presented in the bottom panel. FIG. 7E shows individual sample results for pairs of inflamed and non-inflamed tissue samples from the same individual. Individual identifier numbers and diagnoses, values and standard errors are indicated as in FIGS. 5A-F shows the averaged results for all affected and unaffected samples. Individual identifier numbers and diagnoses, values and standard errors are indicated as in FIGS. 7A-D.

[0017]FIG. 8 shows the genomic DNA sequence including the OCTN1 gene. Locations of exons are highlighted in yellow. Locations of oligonucleotide primer sequences used are highlighted in green (note that the O1X9R primer is the reverse complement of the sequence as shown). Start and stop codons of the coding sequence are highlighted in red. The mutation within exon 9 of the gene is highlighted and is shown with standard DNA nomenclature for polymorphic bases, i.e. “Y” meaning C or T.

[0018]FIG. 9 shows the amino acid sequence as determined from known mRNA sequences for OCTN1. Each letter represents a single amino acid as defined by standard nomenclature. The location of the amino acid change caused by the OCTN1 exon 9 mutation is shown as “(L/F)”, meaning that where the “C” allele is present in genomic DNA, Leucine (“L”) is the corresponding amino acid in the OCTN1 protein, and where the “T” allele is present in genomic DNA, Phenylalanine (“F”) is the corresponding amino acid in the OCTN1 protein.

[0019]FIG. 10 shows in graphical form the expression level of the OCTN1 gene, expressed as relative optical density (“ROD”) of autoradiographic signal from the OCTN1 gene as compared to the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Blue bars represent expression level from RNA extracted from surgically removed non-inflamed GI tract tissue, and red bars represent expression level from RNA extracted from surgically removed inflamed GI tract tissue. Individual RNA samples are identified below the bars with a unique identifier number (e.g. 7403) and patient's diagnosis (“UC” for Ulcerative Colitis, “CD” for Crohn's Disease). Control unaffected samples are labeled as “HC male” and “HC female” and are from individuals without Inflammatory Bowel Disease. FIGS. 10A-C each represent data from a single “Northern blot” (i.e. DNA:RNA hybridization results); for each blot, individual sample results are presented in the top panel and averaged results for inflamed and non-inflamed samples are presented in the bottom panel. In the bottom panel, each bar is labeled with its mean value and standard error of the mean (SEM). Statistical p-values are also presented in the bottom panel. FIG. 10D shows individual sample results for pairs of inflamed and non-inflamed tissue samples from the same individual. Individual identifier numbers and diagnoses are indicated as in FIGS. 10A-C. FIG. 10E shows averaged results for all affected and unaffected samples. Individual identifier numbers and diagnoses, values and standard errors are indicated as in FIGS. 10A-C.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Summary. A functional analysis and in-depth mutation screening of candidate genes was performed in the 250 kb region of chromosome 5q31, described by Rioux J D et al., Nature Genet. 29, 223-228 (2001). Also examined were genes in the region for expression level differences in inflamed and non-inflamed gastrointestinal (GI) tract tissue from Inflammatory Bowel Disease patients. Two genes, OCTN1 (SEQ ID NO:1) and OCTN2 (SEQ ID NO:3), showed significant downregulation in inflamed Crohn's Disease tissue. A coding sequence mutation in the OCTN1 gene that significantly reduces its ability to transport the organic cation carnitine and the prototypical organic cation substrate tetraethyl ammonium (TEA) was detected. Additionally, a mutation in the promoter region of OCTN2 was found to downregulate both basal transcription and transcription induced either by heat shock or arachidonic acid. This transcription difference is apparently due to the disruption of a binding site for heat shock transcription factor 1 (HSF1).

[0021] Mutation detection. For mutation detection and analysis, bidirectional sequencing of polymerase chain reaction (PCR) amplified exons of the OCTN1 and OCTN2 genes was performed on ABI 377 or 3700 sequencers. The detected mutations were verified by visual inspection of both forward and reverse electropherograms. PCR primers for genomic DNA were designed based on the genomic sequences of human OCTN1 and OCTN2 reported in GenBank (loci AC008599 and AC004628 on chromosome 5q). Primers were ˜60 bp upstream or downstream of each exon, allowing sequencing of splice donor and splice acceptor sequences and of the lariat branch site. In the case of the OCTN2 promoter region, PCR amplification of 1.3 kb fragment using PCR primers, two primers, OCTN2 Promoter Forward (O2PF): 5′-CTGCACGGAAATAACTAATCTGTG-3′ (SEQ ID NO:5) and OCTN2 Promoter Reverse (O2PR): 5′-GAGAGGAGCTCGGGTTCAAG-3′ (SEQ ID NO:6) were used. PCR was performed using PCRx Enhancer System (Invitrogen, La Jolla, Calif., USA) with addition of 1× final PCRx Enhancer solution concentration, to overcome the GC-rich nature of this region, and with Platinum Taq DNA Polymerase High Fidelity (Invitrogen, La Jolla, Calif., USA). The PCR protocol includes 30 cycles of 94° C (for 40 sec), 54° C. (for 1 min), and 72° C. (for 2 min) with a 5-min extension at 98° C. at the first cycle and a 10-min extension at 72° C. of the final cycle.

[0022] SNP risk haplotypes were determined from data previously described SNP by Rioux J D et al., Nature Genet. 29: 223-228 (2001), and OCTN1 and OCTN2 mutation data were phased with SNP haplotypes by visual inspection of pedigrees. Significance levels for allele frequency differences between groups (see, TABLE 1, below) were calculated with a two by two chi-squared contingency table. Relative risk calculations (formally, odds ratios) were calculated as described by Bland J M & Altman D G, BMJ 320: 1468 (2000).

[0023] Mutations were initially detected by sequencing of exons, splice junctions and promoter regions of the OCTN1 and-OCTN2 genes from a panel of 16 unrelated patients either heterozygous or homozygous for the Crohn's Disease SNP risk haplotype at 5q31.

[0024] Two mutations that co-segregated with the SNP risk haplotype were identified, a C to T change in exon 9 of OCTN1 that changes the leucine residue at position 503 to phenylalanine (L503F; SEQ ID NO:7), and a G to C change 207 bp 5′ of the start codon of OCTN2 (G-207C; SEQ ID NO:8). The G-207C mutation alters a consensus heat shock transcription factor 1 (HSF1) binding site. Sequencing of other candidate genes in the region did not reveal any mutations consistently found on the risk haplotype background.

[0025] We then sequenced exon 9 of OCTN1 and the promoter region of OCTN2 in individuals from 46 families that were used for previous SNP analysis. Rioux J D et al., Nature Genet. 29, 223-228 (2001). Forty-one of these families segregate at least one copy of the SNP haplotype, and five segregate no copies of this haplotype. Examination of SNP haplotypes in unrelated children from these families revealed that the previously defined SNP risk haplotype always carried both the phenylalanine variant of L503F and the C allele of G-207C.

[0026] We next genotyped these two mutations in a panel of healthy controls, and in a panel of patients known to carry no copies of the SNP risk haplotype. The L503F (SEQ ID NO:7) and G-207C (SEQ ID NO:8) mutant alleles were significantly more common in unrelated patients from these families than in healthy controls, and were almost never found in patients homozygous for the nonrisk haplotype (only one L503F allele in 25 patients (50 chromosomes) and one G-207C allele in 16 patients (32 chromosomes). Allele frequencies in the control group did not deviate from Hardy-Weinberg equilibrium. Allele frequencies are presented in TABLE 1. TABLE 1 ALLELE FREQUENCIES OF OCTN1 AND OCTN2 MUTATIONS Group OCTN1 L503F OCTN2 G-207C healthy controls F allele: 74 (48%) C allele: 93 (50%) I allele: 80 (52%) G allele: 93 (50%) CD patients from risk F allele: 42 (78%) C allele: 37 (77%) haplotype families I allele: 12 (22%) G allele: 11 (23%) p = 0.0003 p = 0.0014 CD patients without risk F allele: 1 (0%) C allele: 1 (3%) haplotype I allele: 49 (98%) G allele: 31 (97%) p < 0.0000001 p = 0.000002

[0027] Numbers of chromosomes are shown for each allele, and the significance level for difference from the healthy control group is shown for the two Crohn's Disease patient groups.

[0028] Odds ratios for Crohn's Disease susceptibility are presented in TABLE 2. TABLE 2 RELATIVE RISK FOR CROHN'S DISEASE Mutation One copy Two copies OCTN1 L503F 5.52 18.67 95% C.I. (0.66-46.20) 95% C.I. (2.25-154.92) OCTN2 G-207C 4.04 14.00 95% C.I. (0.48-33.88) 95% C.I. (1.69-115.84)

[0029] Northern blot analysis. Northern blot analysis of RNA from gastrointestinal tract tissue of Ulcerative Colitis and Crohn's Disease patients revealed a significant downregulation of both OCTN1 and OCTN2 in actively inflamed tissue as compared with uninflamed tissue. To control for variability in expression level between individuals, we also examined matched inflamed and non-inflamed tissue sample pairs from the same patient. The results showed that both OCTN1 and OCTN2 had significant downregulation in inflamed tissue. See, FIG. 1.

[0030] Surgical tissue samples were obtained from patients undergoing scheduled surgical resection for either Crohn's Disease or Ulcerative Colitis. Ethics approval and informed consent were obtained prior to sample collection. Samples were preserved in RNAlater (Ambion) prior to RNA extraction. An adjacent section of tissue was used for standard pathological examination to verify the diagnosis (Crohn's Disease, UC), region of the gastrointestinal tract, and status (inflamed, non-inflamed) of tissue. Control colon RNA from unaffected individuals was purchased from Clontech. Total RNA was extracted from tissue using TRIZOL (Gibco BRL). RNA samples (15 μg per lane) were separated in 1% agarose-3.7% formaldehyde denaturing gel, transferred onto MSI nylon transfer membrane (Osmonics Laboratory Products), and cross-linked by ultraviolet irradiation.

[0031] The membranes were hybridized with ³²P-labeled complementary probes for OCTN1 and OCTN2. OCTN1 transcripts were detected with a 0.8-kb NotI/EcoRI fragment of OCTN1 (ResGen) containing the 5′ part of the coding region of the human OCTN1 gene. OCTN2 transcripts were detected with 2.2 kb NotI/SalI fragment of OCTN1 (ResGen) containing the 3′ part of the coding region of the human OCTN1 gene. Probes were radiolabeled with [α³²P]-dCTP using random priming (Roche Diagnostics GmbH). The unincorporated radiolabeled nucleotides were removed by ProbeQuant G-50 Micro column (Amersham Pharmacia Biotech). The Northern blots containing total RNA from human tissues were hybridized in QuickHyb hybridization solution (Stratagene, La Jolla, Calif., USA) at 68° C. for 2 hrs. The blots were then washed twice in 2×SSC containing 0.1% SDS at room temperature for 15 min and once at 60° C. for 30 min with 0.1×SSC containing 0.1% SDS.

[0032] Densitometry of Northern blots was performed using Scion Imaging Software (Scion Corporation), normalized to G3PDH, and expressed as relative optical density units. Data were analyzed with GraphPad Prism.

[0033] Tissue expression analysis. For expression analysis, RT-PCR of multiple tissue expression panels (Clontech) was performed according to the manufacturer's directions. First-strand cDNA preparations from human gastrointestinal (GI) tract and from human immune system, normalized against several housekeeping genes were used to assess tissue specificity and relative abundance of OCTN1 and OCTN2 mRNA. 5 μl (0.2 ng/μl) of each cDNA were used as a template for RT-PCR using gene-specific primers.

[0034] For OCTN1, the forward primer was 5′-ACCATCGCCAACTTCTCGGC-3′ (SEQ ID NO:9) and the reverse primer was 5′-CTTTCTGCTGCTTCAGGGGA-3′ (SEQ ID NO:10).

[0035] For OCTN2, the forward primer was 5′-CCATCGCCAACTTCTCGG-3′ (SEQ ID NO:11) and the reverse primer was 5′-AATGTTGTGGGACTGCTGCTTC-3′ (SEQ ID NO:12).

[0036] After 32 cycles, 5 μl sample of each PCR product was run on 2% agarose/ethidium bromide gel. G3PDH PCR primers and a control cDNA were used as a positive control.

[0037] RT-PCR expression analysis of multiple tissue panels from the gastrointestinal (GI) tract and immune system of healthy control individuals demonstrated widespread low levels of expression of OCTN1 and OCTN2, with OCTN1 highest in ascending colon and fetal liver, and OCTN2 highest in colon and placenta. RT-PCR results are summarized in TABLE 3. TABLE 3 RT-PCR EXPRESSION ANALYSIS OF OCTN1 ANP OCTN2 Gene GI tract panel Immune system panel OCTN1 low, highest in ascending colon high in fetal liver OCTN2 low, medium in colon low, but high in placenta

[0038] Transient expression of OCTN1 (transporter assays) and OCT2 (luciferase promoter assays). For transient expression of wild-type or mutant (L503F; SEQ ID NO:7), HeLa cells were plated out at a density 1.5×10⁶-10⁵ cells/dish in 100-mm plastic culture dishes (Falcon) and carnitine deficient human fibroblasts, (GM 10665) were plated out at a density 2.5×10⁵ cells/well in 6-well plastic culture dishes (Falcon) 24 hr prior transfection with LipofectAMINE PLUS™ Reagent (Invitrogen, La Jolla, Calif., USA) as recommended by the manufacturer.

[0039] For HeLa cell culture, human HeLa cells were grown in D-MEM supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin. For culture of carnitine deficient human fibroblasts from a patient with primary carnitine deficiency, described by Scaglia F. et al., Genet. Med. 1,34-39 (1998) (see description of the patient GM 10665 in National Institute of General Medical Sciences catalog) were obtained from the National Institute of General Medical Sciences Human Genetic Mutant ell Repository, Coriell Cell Repositories (Camden, N.J., USA). Fibroblasts were grown in D-MEM supplemented with 15% fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin and 1× concentration of non-essential amino acids. Cells were cultured in 37° C. humidified incubator with a mixture of 5% CO₂ and 95% air.

[0040] Forty-eight hr after transfection the media was removed and replaced with Earle's balanced salt solution containing D-glucose (5.5 mM) and supplemented with 0.5% BSA.

[0041] For the OCTN1 transporter assays, carnitine transport measurements were made at room temperature using L-[³H]carnitine as substrate, (specific activity 81 Ci/mmol, Moravek Biochemicals Inc.). The transport buffer was composed of 25 mM HEPES/Tris pH 7.5, supplemented with 140 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl₂, 0.8 mM MgSO4, and 5 mM glucose. The transport medium containing the radiolabeled carnitine were preincubated at 37° C. and then added to the cells. After incubation for 30 min at 37° C., transport was terminated by aspiration of the buffer followed by four washes with ice-cold transport buffer. The cells were then solubilized with 1× cell culture lysis reagent (Promega), and the associated radioactivity was quantitated in a liquid scintillation counter. Cellular protein content was determined according to the bicinchoninic acid method of Smith P K et al., Anal. Biochem. 150: 76-85 (1985), using BCA standard protein assay reagent kit (Pierce). To normalize for the transfection efficiency, cells were co-transfected with 20-fold less firefly luciferase plasmid pGL3-P vector. The luciferase activity was measured on manual luminometer (Lumat LB 9501, Berthold). The cells transfected with empty vector under similar conditions served as control. All assays were carried out in triplicate.

[0042] For the OCTN2 luciferase promoter assays, a Dual-Luciferase Reporter Assay System (Promega) was used to study the effect of the mutation on the OCTN2 promoter region. The OCTN2-promoter luciferase reporter gene constructs were generated by PCR amplification of approximately 2.7 kb OCTN2-promoter fragments using genomic DNA from a patient homozygous for the G allele as a template and ligation into Bg/II/MluI site of the promoterless luciferase vector pRL-null (Promega) that uses luciferase from Renilla reniformis as a reporter. For PCR primers, two primers, OCTN2-BglII:

[0043] 5′-GAAGATCTTGGAAGGCTCAGGTGGGAGG-3′ (SEQ ID NO:13) and OCTN2-M1uI: 5′-CGACGCGTGGCAGCAGGCGACCCAAGAC-3′ (SEQ ID NO:14) were used. PCR was performed using PCRx Enhancer System (Invitrogen, La Jolla, Calif., USA) with addition of 1× final PCRx Enhancer solution concentration and with Platinum Taq DNA Polymerase High Fidelity (Invitrogen, La Jolla, Calif., USA), according to a standard protocol with 30 cycles of 94° C. (for 40 sec), 61° C. (for 1 min), and 72° C. (for 3 min) with a 5-min extension at 98° C. at the first cycle and a 10-min extension at 72° C. of the final cycle.

[0044] The C mutant construct was then created by replacing the 600 bp fragment encompassing the position −207 by digesting it with EcoNI/NdeI, followed by ligation of the corresponding fragment amplified from a patient homozygous for the C allele.

[0045] Constructs were fully sequenced to exclude the possibility of PCR induced errors.

[0046] To normalize the activity of the experimental reporter, constructs were cotransfected into HeLa cells with 20-fold less firefly luciferase plasmid pGL3-P as an internal control LipofectAMINE PLUS™ Reagent (Invitrogen, La Jolla, Calif., USA) as per the manufacturer's protocol. 24 hr after transfection, HeLa cells that were undergoing arachidonate treatment were starved for 6 hr in serum-free medium. After starvation, cells were treated at 37° C. with 20 μM arachidonate for 30 min, followed by 2× wash with PBS. Control cells were treated with an equivalent concentration of ethanol. After that the cells were placed in incubator for additional 18 hr in complete media. Cells that were heat shocked 24 hr after transfection were incubated at 42° C. for 2 hr. Cells were then placed back in 37° C.-incubator for additional 18 hr. The luminescence from (Renilla luciferase reaction (“experimental” reporter a:) was measured simultaneously with the activity of firefly luciferase (“control” reporter) using Dual-Luciferase Reporter Assay System (Promega). The instrumentation used was a manual luminometer (Lumat LB 9501, Berthold). The cells transfected with empty vector under similar conditions served as control. All assays were carried out in triplicate.

[0047] Transfection of the luciferase construct with the C allele of the G-207C mutation of a 2.7 kb fragment of the OCTN2 promoter into HeLa cells resulted in an average 2.8 fold decrease in basal expression as compared with the wild-type (G) allele. Transfection after heat-shock at 42° C. resulted in 3.1 fold reduction of heat shock-induced expression. Transfection after treatment with 20 μM of arachidonic acid at 37° C. also resulted in decreased expression of 3.3 fold as compared to the arachidonate-induced level. Results are presented in FIG. 2.

[0048] For OCTN2 gel shift assays, human HeLa cells were grown in D-MEM supplemented with 10% fetal bovine serum, 2 mm L-glutamate, 100 U/ml penicillin, and 100 μg/ml streptomycin at 37° C. in T-75 tissue culture flasks (Sarstedt). Heat-shocked cells were prepared by incubating the flasks in tissue culture incubator at 42° C. for 3 hr. For arachidonate experiment, the day before, the HeLa cells were starved over night with in serum-free D-MEM. The next day cells were washed twice with PBS. Cells were treated then with for 30 min with 20 mM arachidonate at 37° C. The working concentrations were prepared from sodium arachidonate (Sigma) and stored in cold absolute ethanol as a 100 mM stock solution. Control cells were treated with an equivalent concentration of ethanol. Nuclear extracts were prepared by NP-40 based fractionation. This procedure is a modification of the procedure described by Baler R, Dahl G & Voellmy R, Mol. Cell. Biol. 13: 2486-2496 (1993). Briefly, 2.5×10⁶ cells were pelleted, washed twice in 1×PBS and resuspended in 1 ml low salt buffer (A) containing 10 mM Tris HCl, pH 7.5, 10 mM NaCl, 3 mM MgCl₂, 0.5% Nonidet P-40 (NP-40), 0.5 mM phenylmethylsulfonyl fluoride (PMSF). The nuclei were pellet by centrifugation at 7,000 g for 10 min at 4° C. The supernatant was removed and the pellet (the crude nuclei) was suspended in 50 μl high salt buffer (B), containing 20 mM HEPES, pH 7.5, 5 mM MgCl₂, 0.2 mM EDTA, 1 mM dithiothreitol (DTT), 20% glycerol, 300 mM NaCl, 0.5 mM PMSF. After incubation for 15 min at 4° C. the sample was sonicated for 5 sec, centrifuged at 20,000g for 10 min and the resulting extracts was the nuclear fraction. The nuclear extracts were stored at −80° C. The protein concentration of the extracts was measured using the Bradford assay (Bio-Rad).

[0049] For gel mobility-shift assays (EMSA), the binding reactions were carried out in a 20 μl volume containing 10 μg of nuclear extract, 0.5 ng ³²P-labeled oligonucleotide probe, 1 μg of poly (dI-dC) and 10 μg of BSA, in 10 mM Tris HCl, pH 7.5, 50 mM NaCl, 1 mM DTT, 1 mM EDTA, 5% glycerol for 2 hr on ice. The antibodies supershift experiments were performed by incubating 2 μl of HSF1 and HSF2 antibodies (TransCruz™ Gel Supershift Antibodies), prior addition of the labeled probes. For the competition experiments a 100-fold molar excess of the unlabeled oligonucleotides was added to each reaction. The competitors, used as positive controls were as follows: WT-OCTN2 (P) Antisense:

[0050] 5′-CAGGCCCGGAACCTTCCCTGGTCGT-3′ (SEQ ID NO:15); WT-OCTN2 (P) Sense: 5′-ACGACCAGGGAAGGTTCCGGGCCTG-3′ (SEQ ID NO:16); Mutant OCTN2 (P) Antisense: 5′-CAGGCCCGCAACCTTCCCTGGTCGT-3′ (SEQ ID NO:17); and Mutant OCTN2 (P) Sense: 5′-ACGACCAGGGAAGGTTGCGGGCCTG-3′ (SEQ ID NO:18).

[0051] The design of the oligonucleotides for the typical HSE for human HSP70 were as follows: Sense 5′-TCGGCTGGAATATTCCCGACCTGGCAGCCGA-3′ (SEQ ID NO:19) and Antisense 5′-TCGGCTGCCAGGTCGGGAATATTCCAGCCGA-3′ (SEQ ID NO:20).

[0052] The reaction products were separated electrophoretically on 4% polyacrylamide gel for 3 h at 200 V, dried and exposed to film and detected by autoradiography.

[0053] Gel shift assays of the region surrounding the OCTN2 G-207C promoter mutation demonstrated a specific interaction between a nuclear factor and an oligonucleotide containing the region surrounding the wild-type G allele. Binding to this oligo was specific, in that it could be competed by excess wild-type oligo but not by an oligo containing the mutant C allele, nor by a randomly chosen control oligo unrelated to the OCTN2 promoter. Binding of this factor was induced after incubation at 42° C. and arachidonic acid, but not at 37° C., and was identical in mobility to a factor binding to an oligo corresponding to the heat stress element (HSE) from the HSP70 gene. Binding to the G allele of the OCTN2 promoter was also competed by excess HSP70 HSE oligo, further suggesting that the factor was a heat shock transcription factor. Since the G-207C mutation alters a consensus HSF1 binding site, we hypothesized that this factor was HSF1. Anti-HSF1, but not Anti-HSF2, antibody supershifted the complex, positively identifying the unknown factor as HSF1. HSF1 binding to the OCTN2 promoter was completely abolished by the presence of the C allele under all tested conditions.

[0054] OCTN1 transporter assays. For OCTN1 transport assays, full length OCTN1 cDNA (2.24 kb) was obtained as a full-length genoscope clone ID CS0DJ 003YB03 (ResGen, Invitrogen, La Jolla, Calif., USA). The cDNA clone was subcloned into EcoRI/NotI sites of the pcDNA3 vector. The construct was fully sequenced and found to contain the leucine allele at position 503 (L503). The construct was used as a template for PCR-based site-directed mutagenesis (QuikChange™, Stratagene, La Jolla, Calif., USA) to create the phenylalanine allele (L503F). Parental DNA strands were removed by DpnI digestion, and the nicked circular DNA was used to transform XL-10 Gold supercompetent cells (Stratagene, La Jolla, Calif., USA).

[0055] The mutagenic primers used to prepare the L503F mutant were as follows: 5′-GACTGTCCTGATTGGAATCTTCACCCTTTTTTTCCCTGA-3′ (forward) (SEQ ID NO:21) and 5′-TCAGGGAAAAAAAGGGTGAAGATTCCAATCAGGACAGTC-3′. (reverse) (SEQ ID NO:22)

[0056] The phenylalanine allele of the L503F mutation resulted in a 3.6 fold reduction toward the vector-alone baseline in uptake of radiolabeled carnitine after transient transfection into HeLa cells (FIG. 3A), as compared with an identical construct containing the leucine allele. In a cell line from an individual lacking OCTN2 expression, the OCTN1 L503F mutation resulted in a 5.2-fold reduction toward vector baseline in uptake of radiolabeled carnitine as compared with the leucine allele (FIG. 3B).

[0057] TEA efflux assays: Measurement of efflux of radiolabeled TEA demonstrated that there was a significant decrease in efflux by the CD-associated phenylalanine (L503F) variant of OCTN1 as compared with the leucine variant (L503). See, FIG. 4.

[0058] Transfected Phoenix mouse fibroblast cells were loaded with ¹⁴C-labeled TEA for 30 min. at 37° C., washed twice in cold transport buffer, and then resuspended in transport medium. Efflux was initiated at 37° C. and measured at 0, 4, 8, 12 and 30 minutes. Measurements were taken by washing twice in cold transport buffer, solubilizing with 1× cell culture lysis reagent (Promega) and quantifying the 14C retention from 150 μL aliquots. Cellular protein content was determined according to the BCA method. For sodium-free experiments, cells were suspended in medium with sodium replaced isotonically with N-methyl-D-glucamine.

[0059] Discussion. The two mutations described here co-segregate with the previously described SNP haplotype, are not found on non-risk haplotypes, and contribute to approximately the same degree of genetic susceptibility to Crohn's Disease (TABLE 2). Apparently, Rioux J D et al., Nature Genet. 29: 223-228 (2001) slightly underestimated the genetic risk (i.e., 2-fold genome relative risk for one SNP haplotype, 6-fold for two), likely because the allele frequency of the risk haplotype was previously estimated from non-transmitted parental chromosomes and not from an independent control set, as we have done here.

[0060] The mutation causing the L503F change in OCTN1 has been previously identified as a SNP of unknown function (dbSNP identifier rs1050152), although no allele frequency or functional data was previously available. The L503F mutation is common in the general population. This is likely why the phenylalanine variant (which we show here to be associated with Crohn's Disease susceptibility) was initially reported as the wild-type form of the transporter. Tamai I et al, FEBS Lett. 419, 107-111 (1997). Prior functional assays of the OCTN1 transporter have been performed using the phenylalanine variant, without consideration of other variants at this position, as shown herein.

[0061] For wild-type variants, the amino acid corresponding to position 503 of OCTN1 is either leucine, isoleucine, methionine or valine in all other known organic cation transporters from mouse, rat or human. Burckhardt G & Wolff N A, Am. J. Physiol. Renal. Physiol. 278, F853-F866 (2000). A change to a bulky phenylalanine residue might have a structural effect on the protein. This residue is located in transmembrane domain 11 of OCTN1, in a region previously shown to be involved in carnitine transport. Our transporter assay results show that the leucine variant of OCTN1 is significantly better at transporting carnitine than the phenylalanine variant. This result disagrees with previous functional analysis of OCTN1, which used the phenylalanine variant (Tamai I et al., FEBS Lett. 419, 107-111 (1997)) and which suggested that the in vivo function of OCTN1 may actually be as a carnitine transporter rather than simply as a polyspecific cation transporter.

[0062] In respect of OCTN2, these data shows that basal transcription is downregulated by the C allele of G-207C, and that this allele disrupts the ability of OCTN2 to be upregulated in response to heat shock or arachidonic acid as a result of impaired HSF1 binding and subsequent transcriptional activation.

[0063] The mechanism by which these organic cation transporters contribute to the pathology of Crohn's Disease relate to the in vivo metabolic importance of carnitine. Carnitine facilitates transport of long chain fatty acids across the mitochondrial inner membrane for subsequent β-oxidation, and is also important in the maintenance of cellular CoA levels. Carnitine uptake into lymphocytes, along with a corresponding decrease in plasma levels, is a physiological response to inflammation. Symptoms of the related condition Ulcerative Colitis may be due to an energy deficiency in colonic epithelium secondary to poor mitochondrial function due to decreased long-chain fatty acid transport to the mitochondria. Roediger W E, Lancet 2, 712-715 (1980). The haplotype of mutations in Crohn's Disease patients provided by this invention might affect cellular metabolic energy levels in inflamed tissue by combining impaired OCTN1 transporter function with downregulation and inability to respond to heat or inflammatory stress by the OCTN2 gene.

[0064] Heat shock proteins and arachidonic acids are involved in response to a variety of cellular stresses, including sepsis, metabolic stress and ischaemia. The heat shock response modulates inflammation through modulation of NF-κB activation. OCTN2 has not previously been described as a heat stress inducible protein, but from the results of this invention OCTN2 is a heat stress inducible protein. Thus, the OCTN2 gene is normally upregulated in response to inflammation through binding of HSF1 protein to its promoter. This in turn mobilizes carnitine and bolster metabolism in the inflamed tissue. Impaired OCTN1 carnitine transporter activity and lowered OCTN2 expression level results in reduced metabolism and either trigger or worsen cellular stress in areas of inflammation.

[0065] The two OCTN transporters may therefore function in the inflammatory pathology of Crohn's Disease. Intriguingly, there are reports that topical irrigation of the colon with propyonil-L-carnitine (PLC) can improve some symptoms of Ulcerative Colitis (Giancaterini A et al., Am. J. Gastroenterol. 96, 2275-2276 (2001)), and PLC also inhibits inflammation in various models of vascular inflammation in rodents. Caruso A et al., Pharmacol. Res. 31, 67-72 (1995); Amico-Roxas M et al., Drugs Exp. Clin. Res. 19, 213-217 (1993). Additionally, OCTN1 is a polyspecific cation transporter, and might have a role in the uptake of drugs used to treat CD from the gut. Mutations such as L503F might therefore serve to worsen the condition by reducing bioavailability of therapeutic compounds, or by decreasing the ability of the cell to remove by efflux toxic compounds such as free radicals, toxic metabolites or bacterial toxins.

[0066] Mutations of the OCTN2 gene and uses in diagnosing inflammation. As described above, OCTN2 is a transporter protein with the ability to transport carnitine in a sodium-dependent manner. Missense mutations and nonsense mutations in the organic cation transporter OCTN2 had previously been identified in patients with primary Systemic Carnitine Deficiency (SCD; (OMIM 212 140)), an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycemia and hyperammonemia. By contrast, the invention provides polynucleotide polymorphisms in the OCTN2 gene upstream from the start codon in exon 1 (see, FIG. 6), which are shown here to be related to inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC). The G-207C mutation of OCTN2, identified above, although it reduces basal transcription level also, is most relevant to transcription induced by heat stress or inflammation. In combination with the accompanying OCTN1 mutation, this haplotype of mutations results in susceptibility to Crohn's Disease.

[0067] The invention provides polynucleotide polymorphisms as shown in the following SEQ. ID. NO:23: gtcccgctgccttcctaagccgaScccgggctacctcggtcgtccccagcaggcgtggctggcagaggccgggcctcgccaggtcccc aggacaggccccgcccgggcctcaggtgcactcccggcccgccccgcgccctcgcgtcccgccccagctccgccttcgccggcgccg ctctgcctgccagcggggcgcgccttgcggcccaggcccgSaaccttccctggtcgtgcgccatatgtaaggccagccgcggcaggac caaggcggcggtgtcagctcKcgagcctaccctccgcggacggtcttgggtcKcctgctgcctggcttgcctggtcggcggYRggtg ccccgcgcgcacgcgcaaagcccgccgcgttcccngaccccaggccgcgc.

[0068] The invention also provides other polynucleotide having sequences that are fragments of SEQ ID NO:23. For example, the fragments can have sequences that that are 20 bases long (or multiples thereof).

[0069] Moreover, the invention provides uses for polynucleotides containing the 410 mutation (for example, taagccga(c/g)cccgggcta, SEQ ID NO:24). Alternatively, the invention provides uses for polynucleotides containing the G-207C mutation (for example, ccaggccccg(c/g)aacttccc, SEQ ID NO:25). Other polynucleotides provided by the invention include cggcggtgtcagctc(t/g)cgagcctaccctccgc (SEQ ID NO:26); ggacggtcttgggtc(t/g)cctgctgcctggcttg (SEQ ID NO:27); and cctggtcggcgg(cg/ta)ggtgccccgcgcgcacgc (“TA”; SEQ ID NO:28). Other polynucleotides can be determined from observation of FIG. 6.

[0070] OCTN2 Promoter Region. TABLE 2 shows the allele frequencies of the OCTN2 G-207C promoter region mutation. Data on G-207C polymorphism allele frequencies had not previously been obtained in any populations (healthy or diseased).

[0071] Alleles are listed in TABLE 4 by number (1 or 2) and the DNA nucleotide present at that position (C or G). The number of chromosomes carrying each allele is shown for either unrelated healthy control individuals (“healthy” column) or Crohn's Disease patients from families with genetic risk conferred by the chromosome 5 locus previously described (“CD” column). The frequency of each allele as a percentage of the total is shown in brackets, and the total number of chromosomes (“n”) is shown at the bottom of each column. The results of a 2 by 2 contingency table chi-squared test are presented at the bottom of TABLE 4, demonstrating a significant difference in allele frequency between the “healthy” and “CD” classes (chi-squared statistic of 10.2640, p value with one degree of freedom 0.0014). TABLE 4 ALLELE FREQUENCY DATA FOR OCTN2 G-207C MUTATION allele healthy CD 1 (C) 93 (50%) 37 (77%) 2 (G) 93 (50%) 11 (23%) n = 186 n = 48 chi-squared = 10.2640 p (1df) = 0.0014

[0072] TABLE 5 shows allele frequency data for three polymorphisms of the OCTN2 gene (specifically, the 410, G-207C and “TA” polymorphisms). Allele frequencies are expressed as the number of chromosomes carrying a specific allele followed by the percentage of total chromosomes (“n”) carrying that allele (e.g., for the G-207C mutation in healthy controls, 52 of 110 chromosomes (i.e., 47%) carry the “C” allele). The populations studied are as follows: healthy controls (“healthy”): DNA samples from venous blood of individuals with no history of IBD; RA sibs (“RA”): DNA samples from venous blood of healthy siblings of patients with rheumatoid arthritis but no history of IBD; Wegener's Granulomatosis (“WG”): DNA samples from venous blood of patients with Wegener's Granulomatosis but no history of IBD; surgical cancer/polyp (“cancer”): DNA samples from venous blood of patients undergoing surgery for either colon cancer or colonic polyps but no history of IBD; parents of chr(5) patients: DNA samples from venous blood or cultured white blood cells of parents of CD patients from families showing linkage to chromosome 5; unrelated chr(5) Crohn's Disease (CD) patients (“chr(5) CD”): DNA samples from venous blood or cultured white blood cells of unrelated patients from families showing linkage to chromosome 5; surgical CD: DNA samples from venous blood of patients undergoing surgical removal of bowel tissue as a result of CD; and surgical UC: DNA samples from venous blood of patients undergoing surgical removal of colon tissue as a result of Ulcerative Colitis (UC). TABLE 5 ALLELE FREQUENCIES OF OCTN2 POLYMORPHISMS IN VARIOUS POPULATIONS CONTROL SAMPLES Wegener's surgical cancer/ mutation allele healthy controls RA sibs Granulomatosis polyp G-207C 1 (C) 52 (47%)  8 (44%) 19 (41%) 14 (54%) 2 (G) 58 (53%) 10 (56%) 27 (59%) 12 (46%)  n = 110 n = 18 n = 46 n = 26 410 1 (C) 34 (31%)  3 (21%) 12 (33%)  5 (23%) 2 (G) 76 (69%) 11 (79%) 24 (67%) 17 (77%)  n = 110 n = 14 n = 36 n = 22 TA 1 (CG) 105 (94%)   18 (100)% 42 (96%) 19 (79%) 2 (TA) 7 (6%) 0 (0%) 2 (4%)  5 (21%)  n = 112 n = 18 n = 44 n = 24 CD FAMILY SURGICAL SAMPLES SAMPLES parents of chr(5) unrelated chr(5) surgical surgical mutation allele patients CD patients CD UC G-207C 1 (C) 27 (56%) 35 (76%) 13 (54%) 13 (41%) 2 (G) 21 (44%) 11 (24%) 11 (46%) 19 (59%) n = 48 n = 46 n = 24 n = 32 410 1 (C) 10 (21%)  7 (29%) 11 (42%) 14 (47%) 2 (G) 38 (79%) 17 (71%) 15 (58%) 16 (53%) n = 48 n = 24 n = 26 n = 30 TA 1 (CG)  2 (100%) 18 (90%) 15 (94%) 25 (89%) 2 (TA) 0 (0%)  2 (10%) 1 (6%)  3 (11%) n = 2  n = 20 n = 16 n = 28

[0073] TABLE 6 shows statistical chi-squared analysis of allele frequencies in the populations as described in TABLE 5. The number of alleles present in these populations is as in TABLE 5. For each test, results are shown for the 410, G-207C and “TA” polymorphisms. Compared populations are indicated along the top of each 2 by 2 contingency table (e.g. “healthy”, “c5 patients”), individual alleles are listed to the left and the total number of counted alleles for each polymorphism is shown below the table (e.g. 110 for the G-207C polymorphism in the first such table). To the right of each table (“stats” column) are listed the chi-squared value (top) and the associated p value based on the one-tailed chi-squared distribution with one degree of freedom (e.g. chi-squared for the first such table is 9.7806, and the associated p value is 0.0018). Some populations are grouped together for these analyses. Where this has been done the nomenclature of TABLE 5 has been followed except for the following: “all CD” means “chr(5) CD and surgical CD combined”; and “all IBD” means “chr(5) CD and surgical CD and surgical UC combined”. TABLE 6 STATISTICAL ANALYSES OF ALLELE FREQUENCIES healthy controls vs. healthy controls vs. chr(5) CD patients all CD patients G-207C healthy c5 patients stats G-207C healthy all CD stats 1 52 35 1 52 48 2 58 11 9.7806 2 58 22 7.0203 110 46 0.0018 110 70 0.0081 410 healthy c5 patients 410 healthy all CD 1 34 7 1 34 18 2 76 17 0.0058 2 76 32 0.2072 110 24 0.9393 110 50 0.649 TA healthy c5 patients TA healthy all CD 1 105 18 1 105 33 2 7 2 0.0200 2 7 3 0.0026 112 20 0.8875 112 36 0.9593 healthy controls vs. combined healthy/RA/WG all IBD patients (CD + UC) controls vs. all CD patients G-207C healthy all IDB stats G-207C all controls all CD stats 1 52 61 1 79 48 2 58 41 2.8540 2 95 22 9.8280 110 102 0.0911 174 70 0.0017 410 healthy all IDB 410 all controls all CD 1 34 32 1 49 18 2 76 48 1.3110 2 111 32 0.2894 110 80 0.2522 160 50 0.5906 TA healthy all IDB TA all controls all CD 1 105 58 1 165 33 2 7 6 0.2143 2 9 3 0.1220 112 64 0.6434 174 36 0.7269 combined healthy/RA/WG vs. all controls healthy/RA/WG/ all IBD (CD + UC) cancer vs. chr(5) CD G-207C healthy all IDB stats G-207C all controls c5 patients stats 1 79 61 1 93 35 2 95 41 4.7753 2 107 11 11.9582 174 102 0.0289 200 46 0.0005 410 healthy all IDB 410 all controls c5 patients 1 49 32 1 54 7 2 111 48 1.6981 2 128 17 0.0350 160 80 0.1925 182 24 0.8516 TA healthy all IDB TA all controls c5 patients 1 165 58 1 184 18 2 9 6 1.4290 2 14 2 0.0008 174 64 0.2319 198 20 0.9774

[0074] The most common OCTN2 DNA sequence variation (mutation) identified is significantly increased in frequency in Crohn's Disease patients. This observation is statistically highly significant (p=0.0014). The risk allele is nearly always found on the Single Nucleotide Polymorphism (SNP) risk haplotype background in these patients, fitting our genetic model of Crohn's Disease susceptibility in this region.

[0075] In addition, we have detected an association between the OCTN2 gene and generalized inflammatory responses. We performed a gel shift assay that showed a connection between a mutation in the OCTN2 gene, the specific protein that binds to the promoter region of the OCTN2 gene (HSF1; heat shock transcription factor 1, NCBI UniGene identified Hs.1499), and an HSF1 involvement in inflammation. The specific interaction of the Hsf1 protein with the OCTN2 promoter region is abolished by the presence of the G-207C “C” allele.

[0076] No complexes with wild-type or mutant oligos (with the OCTN2 promoter region abolished by the presence of the G-207C “C” allele) were detected (by hybridization with ³²P-labeled probes) in the absence of nuclear extract. No complexes were formed between wild-type oligo and nuclear extract from cells that are not heat shocked. Wild-type oligo formed a complex with nuclear-extract from heat-shocked cells that is specifically competed for by cold (50× excess over ³²P-labeled test oligonucleotide) wild-type oligo and by cold oligo containing a known heat shock enhancer (HSE). This complex was not competed for by cold mutant oligo or cold unrelated oligo. This complex was identical in gel mobility to the complex between labeled oligo containing a known HSE and nuclear extract. This complex is supershifted, i.e. further reduced in mobility, upon forming a higher-order complex with anti-HSF1 antibody, indicating that the protein component of the nuclear extract that binds to the complex is Hsf1. No complexes are seen between labeled mutant oligo and nuclear extract, regardless of the presence of competitor oligo or anti-Hsf1 antibody.

[0077] Thus, the OCTN2 G-207C mutation forms specific complexes with the HSF1 protein and that the binding of HSF1 is fully abolished by the presence of the G-207C mutant (“C”) allele.

[0078] Thus, the invention provides a method for identifying an anti-inflammatory agent. A complex is formed, in vivo or in vitro, between the heat shock factor 1 (HSF1) protein and a polynucleotide containing a mutation in the OCTN2 promoter region. For example, the mutation can be the G-207C mutation in the OCTN2 promoter region. The complex is contacted with an agent, such as a drug, suspected of dissociating the complex. Detecting the dissociation of the complex identifies the agent as being an agent that is an anti-inflammatory agent.

[0079] Primers useful for PCR amplification parts of the OCTN2 gene include OCTN2 2.4: gccaggttaggttccctttc (SEQ ID NO:29); OCTN2 2.2: agcagcccaaattcttaaagg (SEQ ID NO:30); O2X1v3: gaatcacctcgctgcttttt (SEQ ID NO:31); O2X1v4: aaatgtggaaagggcatct (SEQ ID NO:32); O2X1600up: attaggcggtgtcaagagca (SEQ ID NO:33); O2X1F: ggtcgtgcgccatatgtaag (SEQ ID NO:34); and O2X1R1: gagaggagctcgggttcaag (SEQ ID NO:35).

[0080] Mutations of the OCTN1 gene and uses in diagnosing inflammation. As described above, OCTN1 is a transporter protein with the ability to transport carnitine in a sodium-dependent manner. OCTN1, which has been cloned and characterized in mouse (553 amino acids) and in human fetal liver (551 amino acids), carries a nucleotide binding site motif. OCTN1 is strongly expressed in adult kidney, trachea, bone marrow, and fetal liver, and several tumor cells, but not in adult human liver. OCTN1 mediates uptake of TEA in a pH-dependent manner.

[0081]FIG. 8 shows the nucleotide sequence of the OCTN1 gene, including the single nucleotide polymorphism in exon 9. This polymorphism is represented in dbSNP database as rs1050152. The allele frequency of this SNP had not been determined in any population (control or disease related). The nucleotide sequence of exon 9 is provided as: gtgcttacaacagaatgctgccctacatcgtcatgggtagtctgactgtcctgattggaatcYtcaccctttttttccctgaaagtttgggaatga ctcttccagaaaccttagagcagatgcagaaagtgaaatg (SEQ ID NO:36).

[0082] The nucleotide sequence of the spliced exons is provided as: (SEQ ID NO:37) ccccngnttcgcgccccaatttctaacagcctgcctgtcccccgggaacgttctaacatccttggggagcgccccagctacaagacactgt cctgagaacgctgtcatcacccgtagttgcaagtttcggagcggcagtgggaagcatgcgggactacgacgaggtgatcgccttcctggg cgagtgggggcccttccagcgcctcatcttcttcctgctcagcgccancatcatccccaatggcttcaatggtatgtcagtcgtgttcctggcg gggaccccggagcaccgctgtcgagtgccggacgccgcgaacctgagcnnnnncnngcngaacaacagtgtcccgctgcggctgcg ggacggccgcgaggtgccccacagctgcagccgctaccggctcgccaccatcgccaacttctcggcgctcgggctggagccggggcg cgacgtggacctggggcagctggagcaggagagctgcctggatggctgggagttcagccaggacgtctacctgtccaccgtcgtgaccg agtggaatctggtgtgtgaggacaactggaangtgcccctcaccacctccctgttnttcgtaggcgtgctcctcggctcnttcgtgtccgggc agctgtcagacaggtttggcaggaagaacgttctcttcgcaaccatggctgtacagactggcttcagcttcctgcagattttctccatcagctg ggagatgttcactgtgttatttgtcatcgtgggcatgggccagatctccaactatgtggtagccttcatactaggaacagaaattcttggcaagt cagttcgtattatattctctacattaggagtgtgcacattttttgcagttggctatatgctgctgccactgtttgcttacttcatcagagactggcgg atgctgctgctggcgctgacggtgccgggagtgctgtgtgtcccgctgtggtggttcattcctgaatctccccgatggctgatatcccagaga agatttagagaggctgaagatatcatccaaaaagctgcaaaaatgaacaacanagctgtaccagcagtgatatttgattctgtggaggagct aaatcccctgaagcagcagaaagctttcattctggacctgttcaggactcggaatattgccataatgaccattatgtctttgctgctatggatgct gacctcagtgggttactttgctctgtctctggatgctcctaatttacatggagatgcctacctgaactgtttcctctctgccttgattgaaattccag cttacattacagcctggctgctattgcgaacnctgcccaggcgttatatcatagctgcagtactgttctggggaggaggtgtgcttctcttcatt caactggtacctgtggattattacttcttatccattggtctggtcatgctgggaaaatttgggatcacctctgctttctccatgctgtatgtcttcact gctgagctctacccaaccctggtcaggaacatggcggtgggggtcacatccacggcctccagagtgggcagcatcattgccccctactttg tttacctcggtgcttacaacagaatgctgccctacatcgtcatgggtagtctgactgtcctgattggaatcYtcaccctttttttccctgaaagttt gggaatgactcttccagaaaccttagagcagatgcagaaagtgaaatggttcagatctgggaaaaaaacaagagactcaatggagacana agaaaatcccaaggttctaataactgcattctgaaaaaatatctaccccatttggtgaagtgaaaaacacaaaaataagaccctgtggagaaa ttcgttgttcccactgaaatggactgactgtaacgattgacaccaaaatgaaccttgctatcaagaaatgctcgtcatacagtaaactctggatg attcttccagataatgtccttgctttacaaaccaaccatttctagagagtctccttactcattaattcaatgaaatggattggtaagatgtcttgaaa acatgttagtcaaggactggtaaaatacatataaagattaacactcatttnccaatcatacaaatactatccaaataaaaat.

[0083]FIG. 9 shows the amino acid sequence deduced from the OCTN1 gene including position of the amino acid change caused by the OCTN1 exon 9 mutation (SEQ ID NO:38). Oligonucleotide primers for amplification of OCTN1 exon 9 mutation site include O1X9F: gtgcccagagagtcctccta (SEQ ID NO:39) and O1X9R: ttctccctaaggcattttggt (SEQ ID NO:40).

[0084] TABLE 7 shows the allele frequencies of the OCTN1 exon 9 mutation (see, FIG. 8 and FIG. 9). Alleles are listed by number (1 or 2), the DNA nucleotide present at that position (C or T), and the amino acid encoded by the codon including that nucleotide (Phe for phenylalanine or Leu for leucine). The number of chromosomes carrying each allele is shown for either unrelated healthy control individuals (“healthy” column) or Crohn's Disease patients from families with genetic risk conferred by the chromosome 5 locus previously described (“CD” column). The frequency of each allele as a percentage of the total is shown in brackets, and the total number of chromosomes (“n”) is shown at the bottom of each column. The results of a 2 by 2 contingency table chi-squared test are presented at the bottom of the table demonstrating a significant difference in allele frequency between the “healthy” and “CD” classes (chi-squared statistic of 13.1422, p value with one degree of freedom 0.0003). TABLE 7 ALLELE FREQUENCY DATA FOR OCTN1 EXON 9 MUTATION allele healthy CD 1 (T, Phe) 74 (48%) 42 (78%) 2 (C, Leu) 80 (52%) 12 (22%) n = 154 n = 54 chi-squared = 13.1422 p (1df) = 0.0003

[0085] The invention also provides other polynucleotide having sequences that are fragments of SEQ ID NOS:37 or 38. For example, the fragments can have sequences that that are 20 bases long (or multiples thereof).

[0086] In addition, there may be an association between the OCTN1 gene and generalized inflammatory responses. A specific protein (HSF1) may bind to the promoter region of the OCTN1 gene. Accordingly, inflammatory disease in general is within the scope of the present invention.

[0087] Thus the invention provides a method for identifying an anti-inflammatory agent. A complex is formed, either in vivo or in vitro between the heat shock factor 1 (HSF1) protein and a polynucleotide containing the OCTN1 promoter region. The complex with an agent, such as a drug, suspected of being able to dissociate the complex. Detecting the dissociation of the complex identifies the agent as being an agent that is an anti-inflammatory agent.

[0088] OCTN1 and OCTN2 Polynucleotides. The invention provides polymorphisms of OCTN1 and OCTN2. The term “polynucleotide” encompasses RNA and DNA, including cDNA, genomic DNA, and synthetic (e.g., chemically synthesized) DNA. The polynucleotide may be double-stranded or single-stranded. Where single-stranded, the polynucleotide may be the sense strand or the antisense strand. The polynucleotides of the invention thus provide material for making OCTN1 or OCTN2 polypeptides.

[0089] The polynucleotide of the invention can be used as the basis of drug development diagnostics for Inflammatory Bowel Diseases. In addition to the structural information provided by the polynucleotide of the invention is the associated information provided by the genetic analysis. Methods for using the polynucleotide of the invention in conjunction with further genetic analyses of complex genetic traits are known in the art (see, Lander E. & Kruglyak L., Nature Genet. 11: 241-247 (1995); Ott, J., Nature 379: 772-773 (1996)); as are methods for assessing the relative risk of Crohn's disease for individuals who are heterozygous, homozygous, or compound heterozygous for the identified genetic loci (see, for example, Hugot J.-P., et al., Nature 411: (2001); IBD International Genetics Consortium, Am. J. Hum. Genet. 68: 1165-1171 (2001)).

[0090] By “isolated polynucleotide” is meant DNA that is not immediately contiguous with both of the coding sequences with which it is immediately contiguous (one on the 5′ end and one on the 3′ end) in the naturally occurring genome of the organism from which it is derived. Thus, a recombinant polynucleotide could include some or all of the 5′ non-coding (e.g., promoter) sequences which are immediately contiguous to the coding sequence. The term therefore includes, for example, a recombinant DNA which is incorporated into a vector; into an autonomously replicating plasmid or virus, such as a retrovirus; or into the genomic DNA of a prokaryote or eukaryote, or which exists as a separate molecule (e.g., a cDNA or a genomic DNA fragment produced by PCR or restriction endonuclease treatment) independent of other sequences. It also includes a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence.

[0091] By “substantially identical” is meant a polypeptide or polynucleotide having a sequence that is at least 85%, preferably 90%, and more preferably 95% or more identical to the sequence of the reference amino acid or polynucleotide sequence. For polypeptides, the length of the reference polypeptide sequence will generally be at least 16 amino acids, preferably at least 20 amino acids, more preferably at least 25 amino acids, and most preferably 35 amino acids. For polynucleotides, the length of the reference polynucleotide sequence will generally be at least 50 nucleotides, preferably at least 60 nucleotides, more preferably at least 75 nucleotides, and most preferably at least 110 nucleotides.

[0092] To determine the percent identity of two polynucleotides, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or polynucleotide sequence for optimal alignment with a second amino or polynucleotide sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions (e.g., overlapping positions)×100). Preferably, the two sequences are the same length.

[0093] The determination of percent homology between two sequences can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin & Altschul, Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990), modified as in Karlin & Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993). Such an algorithm is incorporated into the BLASTX and BLASTN programs of Altschul et al., J. Mol. Biol. 215:403-410 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to OCTN2 polynucleotide molecules of the invention. BLAST protein searches can be performed with the BLASTX program, score=50, wordlength=3 to obtain amino acid sequences homologous to OCTN2 protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25: 3389-3402 (1997). Alternatively, PSI-Blast can be used to perform an iterated search that detects distant relationships between molecules. Id. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., BLASTX and BLASTN) can be used. See <http://www.ncbi.nlm.nih.gov>. Another preferred, non-limiting example of a mathematical algorithm used for the comparison of sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0094] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, only exact matches are counted.

[0095] The invention also encompasses polynucleotides that hybridize under stringent conditions to a polynucleotide encoding an OCTN1 or OCTN2 polypeptide. Examples of stringent conditions include: 1) hybridization at 50° C. in Church buffer (7% SDS, 0.5% NaHPO4, 1 mM EDTA, 1% BSA) and washing at 50° C. in 2×SSC; and 2) hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65° C. Other stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, (John Wiley & Sons, N.Y. 1989), 6.3.1-6.3.6. The hybridizing portions of the hybridizing polynucleotides are preferably 20, 30, 50, or 70 bases long. Preferably, the hybridizing portion of the hybridizing polynucleotide is 95% or even 98% identical to the sequence of a portion of a polynucleotide encoding an OCTN2 polypeptide. Hybridizing polynucleotides of the type described above can be used as a cloning probe, a primer (e.g., a PCR primer), or a diagnostic probe. Preferred hybridizing polynucleotides encode a polypeptide having some or all of the biological activities possessed by naturally-occurring OCTN1 or OCTN2. Hybridizing polynucleotides can be splice variants encoded by one of the OCTN1 or OCTN2 genes described herein. Thus, they may encode a protein that is shorter or longer than the various forms of OCTN1 or OCTN2 described herein. Hybridizing polynucleotides may also encode proteins that are related to OCTN1 or OCTN2 (e.g. proteins encoded by genes which include a portion having a relatively high degree of identity to an OCTN1 or OCTN2 gene described herein).

[0096] The invention also features isolated polynucleotide sequences that encode a portion of OCTN1 or OCTN2. Thus, within the invention are polynucleotides encoding fusion proteins in which a portion of OCTN1 or OCTN2 or a portion (e.g., one or more domains) thereof is fused to an unrelated protein or polypeptide (i.e., a fusion partner) to create a fusion protein. Examples of detectable markers include β-lactamase, chloramphenicol acetyltransferase (CAT), alkaline phosphatase (AP), adenosine deaminase (ADA), aminoglycoside phosphotransferase (neo^(r), G418^(r)), dihydrofolate reductase (DHFR), hygromycin-B-phosphotransferase (HPH), thymidine kinase (TK), β-galactosidase, and xanthine guanine phosphoribosyl-transferase (XGPRT).

[0097] The polypeptides of the invention include, but are not limited to, recombinant polypeptides, natural polypeptides produced from polynucleotides of the invention having a polymorphism disclosed herein, and synthetic polypeptides as well as polypeptides which are preproteins or proproteins. The polypeptides of the invention can be expressed fused to another polypeptide, e.g., a marker polypeptide or fusion partner. For example, the polypeptide can be fused to a hexa-histidine tag to facilitate purification of bacterially expressed protein or a hemagglutinin tag to facilitate purification of protein expressed in eukaryotic cells.

[0098] The invention features transformed cells harbouring a polynucleotide encompassed by the invention. The invention also features vectors that include a polynucleotide of the invention that is properly positioned for expression. For example, the vector can be an expression vector, and can include one or more regulatory elements. Regulatory elements that can influence the expression of the polynucleotide inserted into the vector, such as regulatory elements that direct tissue-specific expression, are well known to those of skill in the art. Examples of regulatory elements include the cytomegalovirus hCMV immediate early gene, the early promoter of SV40 adenovirus, the late promoter of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase, the promoters of acid phosphatase, and the promoters of the yeast α-mating factors. The vector can be a plasmid, or a virus, such as a retrovirus.

[0099] By “transformed cell” is meant a cell into which (or into an ancestor of which) has been introduced, by means of recombinant DNA techniques, a DNA molecule encoding (as used herein) an OCTN1 or OCTN2 polypeptide.

[0100] By “positioned for expression” is meant that the selected DNA molecule is positioned adjacent to one or more sequence elements which direct transcription and/or translation of the sequence such that the sequence elements can control transcription and/or translation of the selected DNA (i.e., the selected DNA is operably associated with the sequence elements). Such operably associated elements can be used to facilitate the production of an OCTN1 or OCTN2 polypeptide.

[0101] The invention also features antagonists and agonists of OCTN1 or OCTN2. Antagonists can inhibit one or more of the functions of OCTN1 or OCTN2. Suitable antagonists can include large or small molecules (e.g., organic molecules), antibodies to OCTN1 or OCTN2, and OCTN1 or OCTN2 polypeptides that compete with a native form of OCTN1 or OCTN2. Agonists of OCTN1 or OCTN2 will enhance or facilitate one or more of the functions of OCTN1 or OCTN2. Suitable agonists can include, for example, large or small molecules (e.g., organic molecules), and antibodies to OCTN1 or OCTN2. Also within the invention are polynucleotide molecules that can be used to interfere with OCTN1 or OCTN2 expression, e.g., antisense molecules and ribozymes.

[0102] The invention also features a cell that harbours a recombinant polynucleotide encoding an OCTN1 or OCTN2 polypeptide; a vector which includes a polynucleotide encoding a OCTN2 polypeptide.

[0103] The invention also features a pharmaceutical composition that includes an OCTN1 or OCTN2 polypeptide.

[0104] Methods. The invention features a method for detecting Inflammatory Bowel Diseases. This method includes: (a) obtaining a biological sample; (b) contacting the sample with probe which selectively binds an OCTN1 or OCTN2 polynucleotide; and (c) determining the amount of the probe selectively bound to said biological sample as a measure of the level of expression of v. This level, in turn, serves as a biological marker for disease activity and/or progression in individuals with Inflammatory Bowel Diseases. Thus, the invention provides a method to track or monitor expression level changes in Inflammatory Bowel Diseases as a diagnostic or prognostic tool.

[0105] In general, OCTN1 or OCTN2 proteins and fusion proteins according to the invention can be produced using the polynucleotide of the invention by transformation (transfection, transduction, or infection) of a host cell with all or part of an OCTN1-encoding or OCTN2-encoding DNA fragment (e.g., the cDNA described herein) in a suitable expression vehicle. Suitable expression vehicles include: plasmids, viral particles, and phage. For insect cells, baculovirus expression vectors are suitable. The entire expression vehicle, or a part thereof, can be integrated into the host cell genome. In some circumstances, it is desirable to employ an inducible expression vector, e.g., the LACSWITCH™ Inducible Expression System (Stratagene; La Jolla, Calif., USA).

[0106] Those skilled in the field of molecular biology will understand that any of a wide variety of expression systems can be used to provide the recombinant protein. The precise host cell used is not critical to the invention. The OCTN1 or OCTN2 protein can be produced in a prokaryotic host (e.g., E. coli or B. subtilis) or in a eukaryotic host (e.g., Saccharomyces or Pichia; mammalian cells, e.g., COS, NIH 3T3, CHO, BHK, 293, or HeLa cells; or insect cells).

[0107] Plant cells can also produce proteins and polypeptides. For plant cells viral expression vectors (e.g., cauliflower mosaic virus and tobacco mosaic virus) and plasmid expression vectors (e.g., Ti plasmid) are suitable. Such cells are available from a wide range of sources (e.g., the American Type Culture Collection (ATCC), Manassas, Va., USA.; see also, e.g., Ausubel et al, Current Protocols in Molecular Biology, (John Wiley & Sons, New York, 1994)). The methods of transformation or transfection and the choice of expression vehicle will depend on the host system selected. Transformation and transfection methods are described, e.g., in Ausubel et al. Current Protocols in Molecular Biology, (John Wiley & Sons, New York, 1994); expression vehicles may be chosen from those provided, e.g., in Cloning Vectors: A Laboratory Manual, P. H. Pouwels et al. (1985, Supp. 1987).

[0108] The host cells harboring the expression vehicle can be cultured in conventional nutrient media adapted as needed for activation of a chosen gene, repression of a chosen gene, selection of transformants, or amplification of a chosen gene.

[0109] OCTN1 or OCTN2 polypeptides can be produced as fusion proteins. For example, the expression vector pUR278 (Ruther et al., EMBO J. 2:1791, 1983), can be used to create lacZ fusion proteins. The pGEX vectors can be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can be easily purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0110] In an insect cell expression system, Autographa californica nuclear polyhidrosis virus (AcNPV), which grows in Spodoptera frugiperda cells, is used as a vector to express foreign genes. An OCTN1 or OCTN2 coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter, e.g., the polyhedrin promoter. Successful insertion of a gene encoding an OCTN1 or OCTN2 polypeptide or protein will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat encoded by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted gene is expressed (see, e.g., Smith et al., J. Virol. 46:584, 1983; Smith, U.S. Pat. No. 4,215,051).

[0111] In mammalian host cells, a number of viral-based expression systems can be utilized. In cases where an adenovirus is used as an expression vector, the OCTN1 or OCTN2 polynucleotide sequence can be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion into a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing an OCTN1 or OCTN2 gene product in infected hosts. See, e.g., Logan, Proc. Natl. Acad. Sci. USA 81:3655 (1984).

[0112] Specific initiation signals may also be required for efficient translation of inserted polynucleotide sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where an entire native OCTN1 or OCTN2 gene or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. In other cases, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators. Bittner et al., Methods in Enzymol. 153:516 (1987).

[0113] In addition, a host cell may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in a specific, desired fashion. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product can be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and in particular, choroid plexus cell lines.

[0114] Any technique known in the art can be used to introduce a OCTN2 transgene into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (U.S. Pat. No. 4,873,191); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82:6148 (1985)); gene targeting into embryonic stem cells (Thompson et al., Cell 56:313 (1989)); and electroporation of embryos (Lo, Mol. Cell. Biol. 3:1803, 1983).

[0115] The present invention provides for transgenic animals that carry the OCTN2 transgene in all their cells, as well as animals that carry the transgene in some, but not all of their cells, i.e., mosaic animals. The transgene can be integrated as a single transgene or in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene can also be selectively introduced into and activated in a particular cell type. Lasko et al., Proc. Natl. Acad. Sci. USA 89:6232 (1992). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0116] When it is desired that the OCTN1 or OCTN2 transgene be integrated into the chromosomal site of the endogenous OCTN2 gene, gene targeting is preferred. Briefly, when such a technique is to be used, vectors containing some nucleotide sequences homologous to an endogenous OCTN1 or OCTN2 gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene also can be selectively introduced into a particular cell type, thus inactivating the endogenous OCTN1 or OCTN2 gene in only that cell type. Gu et al., Science 265:103 (1984). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0117] Once transgenic animals have been generated, the expression of the recombinant OCTN1 or OCTN2 gene can be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyse animal tissues to assay whether integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridisation analysis, and RT-PCR. Samples of OCTN1 or OCTN2 gene-expressing tissue also can be evaluated immunocytochemically using antibodies specific for the OCTN1 or OCTN2 transgene product.

[0118] Antisense Polynucleotides. Antisense approaches involve the design of oligonucleotides (either DNA or RNA) that are complementary to OCTN1 or OCTN2 mRNA. The antisense oligonucleotides bind to the complementary OCTN1 or OCTN2 mRNA transcripts and prevent translation. Absolute complementarity, although preferred, is not required. A sequence “complementary” to a portion of an RNA, as referred to herein, means a sequence having sufficient complementarity to be able to hybridise with the RNA, forming a stable duplex; in the case of double-stranded antisense polynucleotides, a single strand of the duplex DNA may be tested, or triplex formation may be assayed. The ability to hybridise will depend on both the degree of complementarily and the length of the antisense polynucleotide. Generally, the longer the hybridising polynucleotide, the more base mismatches with an RNA it may contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridised complex.

[0119] Oligonucleotides that are complementary to the 5′ end of the message, e.g., the 5′ untranslated sequence up to and including the AUG initiation codon, should work most efficiently at inhibiting translation. However, sequences complementary to the 3′ untranslated sequences of mRNAs recently have been shown to be effective at inhibiting translation of mRNAs as well. Wagner, Nature 372:333 (1984). Thus, oligonucleotides complementary to the 5′- or 3′-non-translated, non-coding regions of the OCTN1 or OCTN2 gene, e.g., the human genes shown in FIG. 8 and FIG. 6, could be used in an antisense approach to inhibit translation of endogenous OCTN2 mRNA. Oligonucleotides complementary to the 5′ untranslated region of the mRNA should include the complement of the AUG start codon.

[0120] Antisense oligonucleotides complementary to mRNA coding regions are less efficient inhibitors of translation but could be used in accordance with the invention. Whether designed to hybridise to the 5′-, 3′-, or coding region of OCTN1 or OCTN2 mRNA, antisense polynucleotides should be at least six nucleotides in length, and are preferably oligonucleotides ranging from 6 to about 50 nucleotides in length. In specific aspects the oligonucleotide is at least 10 nucleotides, at least 17 nucleotides, at least 25 nucleotides or at least 50 nucleotides.

[0121] Regardless of the choice of target sequence, it is preferred that in vitro studies are first performed to quantitate the ability of the antisense oligonucleotide to inhibit gene expression. It is preferred that these studies utilize controls that distinguish between antisense gene inhibition and nonspecific biological effects of oligonucleotides. It is also preferred that these studies compare levels of the target RNA or protein with that of an internal control RNA or protein. Additionally, it is envisioned that results obtained using the antisense oligonucleotide are compared with those obtained using a control oligonucleotide. It is preferred that the control oligonucleotide is of approximately the same length as the test oligonucleotide and that the nucleotide sequence of the oligonucleotide differs from the antisense sequence no more than is necessary to prevent specific hybridisation to the target sequence.

[0122] The oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridisation, etc. The oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (as described, e.g., in Letsinger et al., Proc. Natl. Acad. Sci. USA 86:6553 (1989); Lemaitre et al., Proc. Natl. Acad. Sci. USA 84:648 (1987); PCT Publication No. WO 88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134), or hybridisation-triggered cleavage agents (see, e.g., Krol et al., BioTechniques 6:958 (1988)), or intercalating agents (see, e.g., Zon, Pharm. Res. 5:539 (1988)). To this end, the oligonucleotide can be conjugated to another molecule, e.g., a peptide, hybridisation triggered cross-linking agent, transport agent, or hybridisation-triggered cleavage agent.

[0123] The antisense oligonucleotide may comprise at least one modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethyl-aminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-theouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 2-(3-amino-3-N-2-carboxypropl) uracil, (acp3)w, and 2,6-diaminopurine.

[0124] The antisense oligonucleotide may also have at least one modified sugar moiety selected from the group including, but not limited to, arabinose, 2-fluoroarabinose, xylulose, and hexose.

[0125] In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal, or an analog of any of these backbones.

[0126] In yet another embodiment, the antisense oligonucleotide is an α-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other. Gautier et al., Nucl. Acids. Res. 15:6625 (1987). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., Nucl. Acids Res. 15:6131 (1987)), or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327 (1987)).

[0127] Antisense oligonucleotides of the invention can be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. Nucl. Acids Res. 16:3209 (1988), and methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports. Sarin et al., Proc. Natl. Acad. Sci. USA 85:7448 (1988).

[0128] While antisense nucleotides complementary to the OCTN1 or OCTN2 coding region sequence could be used, those complementary to the transcribed untranslated region are most preferred.

[0129] The antisense molecules can be delivered to cells that express OCTN1 or OCTN2 in vivo, e.g., cells of the gastrointestinal tract and the immune system. A number of methods have been developed for delivering antisense DNA or RNA to cells; e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (e.g., antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systemically to achieve intracellular concentrations of the antisense molecule sufficient to suppress translation of endogenous mRNAs and are known in the art.

[0130] Ribozymes. Ribozyme molecules designed to catalytically cleave OCTN1 or OCTN2 mRNA transcripts also can be used to prevent translation of OCTN2 mRNA and expression of OCTN2 (see, e.g., PCT Publication No. WO 90/11364; Saraver et al., Science 247:1222 (1990)). While various ribozymes that cleave mRNA at site-specific recognition sequences can be used to destroy OCTN1 or OCTN2 mRNAs, the use of hammerhead ribozymes is preferred. Hammerhead ribozymes cleave mRNAs at locations dictated by flanking regions that form complementary base pairs with the target mRNA. The sole requirement is that the target its mRNA have the following sequence of two bases: 5′-UG-3′. The construction and production of hammerhead ribozymes is well known in the art. Haseloff et al., Nature 334:585 (1988).

[0131] The ribozymes of the invention also include RNA endoribonucleases (hereinafter “Cech-type ribozymes”), such as the one that occurs naturally in Tetrahymena thermophila (known as the IVS or L-19 IVS RNA), and which has been extensively described by Cech and his collaborators. Zaug et al., Science 224:574 (1984); Zaug et al., Science 231:470 (1986); Zug et al., Nature 324:429 (1986); PCT Application No. WO 88/04300; and Been et al., Cell 47:207 (1986). The Cech-type ribozymes have an eight base-pair sequence that hybridises to a target RNA sequence, whereafter cleavage of the target RNA takes place. The invention encompasses those Cech-type ribozymes that target eight base-pair active site sequences present in OCTN2.

[0132] Methods for Modulating OCTN1 or OCVN2 Expression. Endogenous OCTN1 or OCTN2 gene expression can also be reduced by inactivating or “knocking out” the OCTN1 or OCTN2 gene or its promoter using targeted homologous recombination (see, e.g., U.S. Pat. No. 5,464,764). For example, a mutant, non-functional OCTN2 (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous OCTN2 gene (either the coding regions or regulatory regions of the OCTN2 gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express OCTN2 in vivo. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the OCTN1 or OCTN2 gene. Such approaches are particularly suited for use in the agricultural field where modifications to ES (embryonic stem) cells can be used to generate animal offspring with an inactive OCTN1 or OCTN2. However, this approach can be adapted for use in humans, provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors, e.g., herpes virus vectors for delivery to brain tissue; e.g., the arcuate nucleus or the choroid plexus.

[0133] In another embodiment, modulators of OCTN1 or OCTN2 expression are identified in a method in which a cell is contacted with a candidate compound and the expression of OCTN1 or OCTN2 mRNA or protein in the cell is determined. The level of expression of OCTN1 or OCTN2 mRNA or protein in the presence of the candidate compound is compared to the level of expression of OCTN1 or OCTN2 mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of OCTN1 or OCTN2 expression based on this comparison. For example, when expression of OCTN1 or OCTN2 mRNA or protein is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of OCTN1 or OCTN2 mRNA or protein expression. Alternatively, when expression of OCTN1 or OCTN2 mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of OCTN1 or OCTN2 mRNA or protein expression. The level of OCTN1 or OCTN2 mRNA or protein expression in the cells can be determined by methods described herein for detecting OCTN1 or OCTN2 mRNA or protein.

[0134] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al., Proc. Natl. Acad. Sci. USA 90:6909 (1993); Erb et al., Proc. Natl. Acad. Sci. USA 91:11422 (1994); Zuckermann et al., J. Med. Chem. 37:2678 (1994); Cho et al., Science 261:1303 (1993); Carrell et al., Angew. Chem. Int. Ed. Engl. 33:2059 (1994); Carell et al., Angew. Chem. Int. Ed. Engl. 33:2061 (1994); and Gallop et al., J. Med. Chem. 37:1233 (1994).

[0135] Libraries of compounds may be presented in solution (e.g., Houghten, Bio/Techniques 13:412-421 (1992)), or on beads (Lam, Nature 354:82-84 (1991)), chips (Fodor, Nature 364:555-556 (1993)), bacteria (U.S. Pat. No.5,223,409), spores (U.S. Pat. Nos. 5,571,698; 5,403,484; and 5,223,409), plasmids (Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869 (1992)) or phage (Scott & Smith, Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310 (1991).

[0136] Diagnostic Applications. The polynucleotides, polypeptides, and antibodies of the invention are useful for identifying those compartments of mammalian cells that contain proteins important to the function of OCTN1 or OCTN2. Antibodies specific for OCTN1 or OCTN2 may be produced as described above. The normal location of the protein is then determined either in situ or using fractionated cells by any standard immunological or immunohistochemical procedure (see, e.g., Ausubel et al., supra; Bancroft & Stevens, Theory and Practice of Histological Techniques, (Churchill Livingstone, 1982).

[0137] Alternatively, OCTN1 or OCTN2 expression can be assayed by standard Northern blot analysis or can be aided by PCR (see, e.g., Ausubel et al., supra; PCR Technology: Principles and Applications for DNA Amplification, ed., H. A. Ehrlich (Stockton Press, N.Y.). Also, see above for working examples. If desired or necessary, analysis can be carried out to detect point mutations in the OCTN2 sequence (for example, using well-known polynucleotide mismatch detection techniques). All of the above techniques are enabled by the OCTN1 or OCTN2 sequences described herein.

[0138] Accordingly, the polynucleotides, polypeptides and antibodies of the invention can be used in a method for determining whether a patient has a disorder associated with abnormal expression of OCTN1 or OCTN2. The method can be carried out by quantitating the level of expression of OCTN1 or OCTN2 in a biological sample obtained from the patient. As a control, the quantitation can be carried out using a biological sample obtained from a subject who is healthy.

[0139] OCTN1 or OCTN2 expression can be assessed at the level of gene expression, for example, by quantitating the level of OCTN1 or OCTN2 mRNA expression in the biological sample, or at the level of protein expression, by quantitating the level of OCTN1 or OCTN2 protein expressed. Quantitation can be carried out using the techniques described above, which are well within the abilities of those of skill in the art to perform.

[0140] Should it be determined that a patient has a disorder that is associated with abnormal expression or activity of OCTN1 or OCTN2, the patient can be given a compound that modulates that expression or activity. For example, the patient can receive a compound such as a small molecule, an antisense polynucleotide molecule, or a ribozyme, that inhibits the expression of OCTN2. The patient can also receive a compound that inhibits the activity of OCTN1 or OCTN2. An antibody that specifically binds OCTN1 or OCTN2 can be used for this purpose. Alternatively, the patient can receive a compound that enhances the expression or activity of OCTN2. Compounds that inhibit or enhance the expression or activity of OCTN2 can include synthetic molecules. These methods of treatment can be used to treat Inflammatory Bowel Diseases and related disorders associated with cellular proliferation.

[0141] The details of one or more embodiments of the invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.

[0142] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the invention to the precise form disclosed, but by the claims appended hereto.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 42 <210> SEQ ID NO 1 <211> LENGTH: 2214 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (166)..(1821) <223> OTHER INFORMATION: <400> SEQUENCE: 1 cctgtttccc aggaacggtc cccggcttcg cgccccaatt tctaacagcc tgcctgtccc 60 ccgggaacgt tctaacatcc ttggggagcg ccccagctac aagacactgt cctgagaacg 120 ctgtcatcac ccgtagttgc aagtttcgga gcggcagtgg gaagc atg cgg gac tac 177 Met Arg Asp Tyr 1 gac gag gtg atc gcc ttc ctg ggc gag tgg ggg ccc ttc cag cgc ctc 225 Asp Glu Val Ile Ala Phe Leu Gly Glu Trp Gly Pro Phe Gln Arg Leu 5 10 15 20 atc ttc ttc ctg ctc agc gcc agc atc atc ccc aat ggc ttc aat ggt 273 Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn Gly Phe Asn Gly 25 30 35 atg tca gtc gtg ttc ctg gcg ggg acc ccg gag cac cgc tgt cga gtg 321 Met Ser Val Val Phe Leu Ala Gly Thr Pro Glu His Arg Cys Arg Val 40 45 50 ccg gac gcc gcg aac ctg agc agc gcc tgg cgc aac aac agt gtc ccg 369 Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn Asn Ser Val Pro 55 60 65 ctg cgg ctg cgg gac ggc cgc gag gtg ccc cac agc tgc agc cgc tac 417 Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser Cys Ser Arg Tyr 70 75 80 cgg ctc gcc acc atc gcc aac ttc tcg gcg ctc ggg ctg gag ccg ggg 465 Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly Leu Glu Pro Gly 85 90 95 100 cgc gac gtg gac ctg ggg cag ctg gag cag gag agc tgc ctg gat ggc 513 Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser Cys Leu Asp Gly 105 110 115 tgg gag ttc agc cag gac gtc tac ctg tcc acc gtc gtg acc gag tgg 561 Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Val Val Thr Glu Trp 120 125 130 aat ctg gtg tgt gag gac aac tgg aag gtg ccc ctc acc acc tcc ctg 609 Asn Leu Val Cys Glu Asp Asn Trp Lys Val Pro Leu Thr Thr Ser Leu 135 140 145 ttc ttc gta ggc gtg ctc ctc ggc tcc ttc gtg tcc ggg cag ctg tca 657 Phe Phe Val Gly Val Leu Leu Gly Ser Phe Val Ser Gly Gln Leu Ser 150 155 160 gac agg ttt ggc agg aag aac gtt ctc ttc gca acc atg gct gta cag 705 Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Ala Thr Met Ala Val Gln 165 170 175 180 act ggc ttc agc ttc ctg cag att ttc tcc atc agc tgg gag atg ttc 753 Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Ile Ser Trp Glu Met Phe 185 190 195 act gtg tta ttt gtc atc gtg ggc atg ggc cag atc tcc aac tat gtg 801 Thr Val Leu Phe Val Ile Val Gly Met Gly Gln Ile Ser Asn Tyr Val 200 205 210 gta gcc ttc ata cta gga aca gaa att ctt ggc aag tca gtt cgt att 849 Val Ala Phe Ile Leu Gly Thr Glu Ile Leu Gly Lys Ser Val Arg Ile 215 220 225 ata ttc tct aca tta gga gtg tgc aca ttt ttt gca gtt ggc tat atg 897 Ile Phe Ser Thr Leu Gly Val Cys Thr Phe Phe Ala Val Gly Tyr Met 230 235 240 ctg ctg cca ctg ttt gct tac ttc atc aga gac tgg cgg atg ctg ctg 945 Leu Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp Arg Met Leu Leu 245 250 255 260 ctg gcg ctg acg gtg ccg gga gtg ctg tgt gtc ccg ctg tgg tgg ttc 993 Leu Ala Leu Thr Val Pro Gly Val Leu Cys Val Pro Leu Trp Trp Phe 265 270 275 att cct gaa tct ccc cga tgg ctg ata tcc cag aga aga ttt aga gag 1041 Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Arg Arg Phe Arg Glu 280 285 290 gct gaa gat atc atc caa aaa gct gca aaa atg aac aac ata gct gta 1089 Ala Glu Asp Ile Ile Gln Lys Ala Ala Lys Met Asn Asn Ile Ala Val 295 300 305 cca gca gtg ata ttt gat tct gtg gag gag cta aat ccc ctg aag cag 1137 Pro Ala Val Ile Phe Asp Ser Val Glu Glu Leu Asn Pro Leu Lys Gln 310 315 320 cag aaa gct ttc att ctg gac ctg ttc agg act cgg aat att gcc ata 1185 Gln Lys Ala Phe Ile Leu Asp Leu Phe Arg Thr Arg Asn Ile Ala Ile 325 330 335 340 atg acc att atg tct ttg ctg cta tgg atg ctg acc tca gtg ggt tac 1233 Met Thr Ile Met Ser Leu Leu Leu Trp Met Leu Thr Ser Val Gly Tyr 345 350 355 ttt gct ctg tct ctg gat gct cct aat tta cat gga gat gcc tac ctg 1281 Phe Ala Leu Ser Leu Asp Ala Pro Asn Leu His Gly Asp Ala Tyr Leu 360 365 370 aac tgt ttc ctc tct gcc ttg att gaa att cca gct tac att aca gcc 1329 Asn Cys Phe Leu Ser Ala Leu Ile Glu Ile Pro Ala Tyr Ile Thr Ala 375 380 385 tgg ctg cta ttg cga acc ctg ccc agg cgt tat atc ata gct gca gta 1377 Trp Leu Leu Leu Arg Thr Leu Pro Arg Arg Tyr Ile Ile Ala Ala Val 390 395 400 ctg ttc tgg gga gga ggt gtg ctt ctc ttc att caa ctg gta cct gtg 1425 Leu Phe Trp Gly Gly Gly Val Leu Leu Phe Ile Gln Leu Val Pro Val 405 410 415 420 gat tat tac ttc tta tcc att ggt ctg gtc atg ctg gga aaa ttt ggg 1473 Asp Tyr Tyr Phe Leu Ser Ile Gly Leu Val Met Leu Gly Lys Phe Gly 425 430 435 atc acc tct gct ttc tcc atg ctg tat gtc ttc act gct gag ctc tac 1521 Ile Thr Ser Ala Phe Ser Met Leu Tyr Val Phe Thr Ala Glu Leu Tyr 440 445 450 cca acc ctg gtc agg aac atg gcg gtg ggg gtc aca tcc acg gcc tcc 1569 Pro Thr Leu Val Arg Asn Met Ala Val Gly Val Thr Ser Thr Ala Ser 455 460 465 aga gtg ggc agc atc att gcc ccc tac ttt gtt tac ctc ggt gct tac 1617 Arg Val Gly Ser Ile Ile Ala Pro Tyr Phe Val Tyr Leu Gly Ala Tyr 470 475 480 aac aga atg ctg ccc tac atc gtc atg ggt agt ctg act gtc ctg att 1665 Asn Arg Met Leu Pro Tyr Ile Val Met Gly Ser Leu Thr Val Leu Ile 485 490 495 500 gga atc ctc acc ctt ttt ttc cct gaa agt ttg gga atg act ctt cca 1713 Gly Ile Leu Thr Leu Phe Phe Pro Glu Ser Leu Gly Met Thr Leu Pro 505 510 515 gaa acc tta gag cag atg cag aaa gtg aaa tgg ttc aga tct ggg aaa 1761 Glu Thr Leu Glu Gln Met Gln Lys Val Lys Trp Phe Arg Ser Gly Lys 520 525 530 aaa aca aga gac tca atg gag aca gaa gaa aat ccc aag gtt cta ata 1809 Lys Thr Arg Asp Ser Met Glu Thr Glu Glu Asn Pro Lys Val Leu Ile 535 540 545 act gca ttc tga aaaaatatct accccatttg gtgaagtgaa aaacagaaaa 1861 Thr Ala Phe 550 ataagaccct gtggagaaat tcgttgttcc cactgaaatg gactgactgt aacgattgac 1921 accaaaatga accttgctat caagaaatgc tcgtcataca gtaaactctg gatgattctt 1981 ccagataatg tccttgcttt acaaaccaac catttctaga gagtctcctt actcattaat 2041 tcaatgaaat ggattggtaa gatgtcttga aaacatgtta gtcaaggact ggtaaaatac 2101 atataaagat taacactcat ttccaatcat acaaatacta tccaaataaa aataacatca 2161 ttgtattaac gcaaatatta ggtgacaaca aaaaaaaaaa aaaaaaaaaa aaa 2214 <210> SEQ ID NO 2 <211> LENGTH: 551 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Arg Asp Tyr Asp Glu Val Ile Ala Phe Leu Gly Glu Trp Gly Pro 1 5 10 15 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn 20 25 30 Gly Phe Asn Gly Met Ser Val Val Phe Leu Ala Gly Thr Pro Glu His 35 40 45 Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn 50 55 60 Asn Ser Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser 65 70 75 80 Cys Ser Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly 85 90 95 Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser 100 105 110 Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Val 115 120 125 Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asn Trp Lys Val Pro Leu 130 135 140 Thr Thr Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Val Ser 145 150 155 160 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Ala Thr 165 170 175 Met Ala Val Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Ile Ser 180 185 190 Trp Glu Met Phe Thr Val Leu Phe Val Ile Val Gly Met Gly Gln Ile 195 200 205 Ser Asn Tyr Val Val Ala Phe Ile Leu Gly Thr Glu Ile Leu Gly Lys 210 215 220 Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Thr Phe Phe Ala 225 230 235 240 Val Gly Tyr Met Leu Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp 245 250 255 Arg Met Leu Leu Leu Ala Leu Thr Val Pro Gly Val Leu Cys Val Pro 260 265 270 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Arg 275 280 285 Arg Phe Arg Glu Ala Glu Asp Ile Ile Gln Lys Ala Ala Lys Met Asn 290 295 300 Asn Ile Ala Val Pro Ala Val Ile Phe Asp Ser Val Glu Glu Leu Asn 305 310 315 320 Pro Leu Lys Gln Gln Lys Ala Phe Ile Leu Asp Leu Phe Arg Thr Arg 325 330 335 Asn Ile Ala Ile Met Thr Ile Met Ser Leu Leu Leu Trp Met Leu Thr 340 345 350 Ser Val Gly Tyr Phe Ala Leu Ser Leu Asp Ala Pro Asn Leu His Gly 355 360 365 Asp Ala Tyr Leu Asn Cys Phe Leu Ser Ala Leu Ile Glu Ile Pro Ala 370 375 380 Tyr Ile Thr Ala Trp Leu Leu Leu Arg Thr Leu Pro Arg Arg Tyr Ile 385 390 395 400 Ile Ala Ala Val Leu Phe Trp Gly Gly Gly Val Leu Leu Phe Ile Gln 405 410 415 Leu Val Pro Val Asp Tyr Tyr Phe Leu Ser Ile Gly Leu Val Met Leu 420 425 430 Gly Lys Phe Gly Ile Thr Ser Ala Phe Ser Met Leu Tyr Val Phe Thr 435 440 445 Ala Glu Leu Tyr Pro Thr Leu Val Arg Asn Met Ala Val Gly Val Thr 450 455 460 Ser Thr Ala Ser Arg Val Gly Ser Ile Ile Ala Pro Tyr Phe Val Tyr 465 470 475 480 Leu Gly Ala Tyr Asn Arg Met Leu Pro Tyr Ile Val Met Gly Ser Leu 485 490 495 Thr Val Leu Ile Gly Ile Leu Thr Leu Phe Phe Pro Glu Ser Leu Gly 500 505 510 Met Thr Leu Pro Glu Thr Leu Glu Gln Met Gln Lys Val Lys Trp Phe 515 520 525 Arg Ser Gly Lys Lys Thr Arg Asp Ser Met Glu Thr Glu Glu Asn Pro 530 535 540 Lys Val Leu Ile Thr Ala Phe 545 550 <210> SEQ ID NO 3 <211> LENGTH: 3252 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (222)..(1895) <223> OTHER INFORMATION: <400> SEQUENCE: 3 gcggcccagg cccgcaacct tccctggtcg tgcgccctat gtaaggccag ccgcggcagg 60 accaaggcgg cggtgtcagc tcgcgagcct accctccgcg gacggtcttg ggtcgcctgc 120 tgcctggctt gcctggtcgg cggcgggtgc cccgcgcgca cgcgcaaagc ccgccgcgtt 180 ccccgacccc aggccgcgct ctgtgggcct ctgagggcgg c atg cgg gac tac gac 236 Met Arg Asp Tyr Asp 1 5 gag gtg acc gcc ttc ctg ggc gag tgg ggg ccc ttc cag cgc ctc atc 284 Glu Val Thr Ala Phe Leu Gly Glu Trp Gly Pro Phe Gln Arg Leu Ile 10 15 20 ttc ttc ctg ctc agc gcc agc atc atc ccc aat ggc ttc acc ggc ctg 332 Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn Gly Phe Thr Gly Leu 25 30 35 tcc tcc gtg ttc ctg ata gcg acc ccg gag cac cgc tgc cgg gtg ccg 380 Ser Ser Val Phe Leu Ile Ala Thr Pro Glu His Arg Cys Arg Val Pro 40 45 50 gac gcc gcg aac ctg agc agc gcc tgg cgc aac cac act gtc cca ctg 428 Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn His Thr Val Pro Leu 55 60 65 cgg ctg cgg gac ggc cgc gag gtg ccc cac agc tgc cgc cgc tac cgg 476 Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser Cys Arg Arg Tyr Arg 70 75 80 85 ctc gcc acc atc gcc aac ttc tcg gcg ctt ggg ctg gag ccg ggg cgc 524 Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly Leu Glu Pro Gly Arg 90 95 100 gac gtg gac ctg ggg cag ctg gag cag gag agc tgt ctg gat ggc tgg 572 Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser Cys Leu Asp Gly Trp 105 110 115 gag ttc agt cag gac gtc tac ctg tcc acc att gtg acc gag tgg aac 620 Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Ile Val Thr Glu Trp Asn 120 125 130 ctg gtg tgt gag gac gac tgg aag gcc cca ctc aca atc tcc ttg ttc 668 Leu Val Cys Glu Asp Asp Trp Lys Ala Pro Leu Thr Ile Ser Leu Phe 135 140 145 ttc gtg ggt gtg ctg ttg ggc tcc ttc att tca ggg cag ctg tca gac 716 Phe Val Gly Val Leu Leu Gly Ser Phe Ile Ser Gly Gln Leu Ser Asp 150 155 160 165 agg ttt ggc cgg aag aat gtg ctg ttc gtg acc atg ggc atg cag aca 764 Arg Phe Gly Arg Lys Asn Val Leu Phe Val Thr Met Gly Met Gln Thr 170 175 180 ggc ttc agc ttc ctg cag atc ttc tcg aag aat ttt gag atg ttt gtc 812 Gly Phe Ser Phe Leu Gln Ile Phe Ser Lys Asn Phe Glu Met Phe Val 185 190 195 gtg ctg ttt gtc ctt gta ggc atg ggc cag atc tcc aac tat gtg gca 860 Val Leu Phe Val Leu Val Gly Met Gly Gln Ile Ser Asn Tyr Val Ala 200 205 210 gca ttt gtc ctg ggg aca gaa att ctt ggc aag tca gtt cgt ata ata 908 Ala Phe Val Leu Gly Thr Glu Ile Leu Gly Lys Ser Val Arg Ile Ile 215 220 225 ttc tct acg tta gga gtg tgc ata ttt tat gca ttt ggc tac atg gtg 956 Phe Ser Thr Leu Gly Val Cys Ile Phe Tyr Ala Phe Gly Tyr Met Val 230 235 240 245 ctg cca ctg ttt gct tac ttc atc cga gac tgg cgg atg ctg ctg gtg 1004 Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp Arg Met Leu Leu Val 250 255 260 gcg ctg acg atg ccg ggg gtg cta tgc gtg gca ctc tgg tgg ttc atc 1052 Ala Leu Thr Met Pro Gly Val Leu Cys Val Ala Leu Trp Trp Phe Ile 265 270 275 cct gag tcc ccc cga tgg ctc atc tct cag gga cga ttt gaa gag gca 1100 Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Gly Arg Phe Glu Glu Ala 280 285 290 gag gtg atc atc cgc aag gct gcc aaa gcc aat ggg att gtt gtg cct 1148 Glu Val Ile Ile Arg Lys Ala Ala Lys Ala Asn Gly Ile Val Val Pro 295 300 305 tcc act atc ttt gac ccg agt gag tta caa gac cta agt tcc aag aag 1196 Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln Asp Leu Ser Ser Lys Lys 310 315 320 325 cag cag tcc cac aac att ctg gat ctg ctt cga acc tgg aat atc cgg 1244 Gln Gln Ser His Asn Ile Leu Asp Leu Leu Arg Thr Trp Asn Ile Arg 330 335 340 atg gtc acc atc atg tcc ata atg ctg tgg atg acc ata tca gtg ggc 1292 Met Val Thr Ile Met Ser Ile Met Leu Trp Met Thr Ile Ser Val Gly 345 350 355 tat ttt ggg ctt tcg ctt gat act cct aac ttg cat ggg gac atc ttt 1340 Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn Leu His Gly Asp Ile Phe 360 365 370 gtg aac tgc ttc ctt tca gcg atg gtt gaa gtc cca gca tat gtg ttg 1388 Val Asn Cys Phe Leu Ser Ala Met Val Glu Val Pro Ala Tyr Val Leu 375 380 385 gcc tgg ctg ctg ctg caa tat ttg ccc cgg cgc tat tcc atg gcc act 1436 Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg Arg Tyr Ser Met Ala Thr 390 395 400 405 gcc ctc ttc ctg ggt ggc agt gtc ctt ctc ttc atg cag ctg gta ccc 1484 Ala Leu Phe Leu Gly Gly Ser Val Leu Leu Phe Met Gln Leu Val Pro 410 415 420 cca gac ttg tat tat ttg gct aca gtc ctg gtg atg gtg ggc aag ttt 1532 Pro Asp Leu Tyr Tyr Leu Ala Thr Val Leu Val Met Val Gly Lys Phe 425 430 435 gga gtc acg gct gcc ttt tcc atg gtc tac gtg tac aca gcc gag ctg 1580 Gly Val Thr Ala Ala Phe Ser Met Val Tyr Val Tyr Thr Ala Glu Leu 440 445 450 tat ccc aca gtg gtg aga aac atg ggt gtg gga gtc agc tcc aca gca 1628 Tyr Pro Thr Val Val Arg Asn Met Gly Val Gly Val Ser Ser Thr Ala 455 460 465 tcc cgc ctg ggc agc atc ctg tct ccc tac ttc gtt tac ctt ggt gcc 1676 Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr Phe Val Tyr Leu Gly Ala 470 475 480 485 tac gac cgc ttc ctg ccc tac att ctc atg gga agt ctg acc atc ctg 1724 Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met Gly Ser Leu Thr Ile Leu 490 495 500 aca gcc atc ctc acc ttg ttt ctc cca gag agc ttc ggt acc cca ctc 1772 Thr Ala Ile Leu Thr Leu Phe Leu Pro Glu Ser Phe Gly Thr Pro Leu 505 510 515 cca gac acc att gac cag atg cta aga gtc aaa gga atg aaa cac aga 1820 Pro Asp Thr Ile Asp Gln Met Leu Arg Val Lys Gly Met Lys His Arg 520 525 530 aaa act cca agt cac aca agg atg tta aaa gat ggt caa gaa agg ccc 1868 Lys Thr Pro Ser His Thr Arg Met Leu Lys Asp Gly Gln Glu Arg Pro 535 540 545 aca atc ctt aaa agc aca gcc ttc taa catcgcttcc agtaagggag 1915 Thr Ile Leu Lys Ser Thr Ala Phe 550 555 aaactgaaga ggaaagactg tcttgccaga aatggccagc ttgtgcagac tccgagtcct 1975 tcagtgacaa aggcctttgc tgtttgtcct cttgacctgt gtctgacttg ctcctggatg 2035 ggcacccaca ctcagaggct acatatggcc ctagagcacc accttcctct agggacactg 2095 gggctaccta cagacaactt catctaagtc ctaactatta caatgatgga ctcagcacct 2155 ccaaagcagt taatttttca ctagaaccag tgagatctgg aggaatgtga gaagcatatg 2215 ctaaatgtac attttaattt tagactactt gaaaaggccc ctaataaggc tagaggtcta 2275 agtcccccac ccctttcccc actcccctct agtggtgaac tttagaggaa aaggaagtaa 2335 ttgcacaagg agtttgattc ttaccttttc tcagttacag aggacattaa ctggatcatt 2395 gcttccccag ggcaggagag cgcagagcta gggaaagtga aaggtaatga agatggagca 2455 gaatgagcag atgcagatca ccagcaaagt gcactgatgt gtgagctctt aagaccactc 2515 agcatgacga ctgagtagac ttgtttacat ctgatcaaag cactgggctt gtccaggctc 2575 ataataaatg ctccattgaa tctactattc ttgttttcca ctgctgtgga aacctccttg 2635 ctactatagc gtcttatgta tggtttaaag gaaatttatc aggtgagaga gatgagcaac 2695 gttgtctttt ctctcaaagc tgtaatgtgg gttttgtttt attgtttatt tgtttgttgt 2755 tgtatccttt tctccttgtt atttgccctt cagaatgcac ttgggaaagg ctggttcctt 2815 agcctcctgg tttgtgtctt tttttttttt tttttaaaca cagaatcact ctggcaattg 2875 tctgcagctg ccactggtgc aaggccttac cagccctagc ctctagcact tctctaagtg 2935 ccaaaaacag tgtcattgtg tgtgttcctt tcttgatact tagtcatggg aggatattac 2995 aaaaaagaaa tttaaattgt gttcatagtc tttcagagta gctcacttta gtcctgtaac 3055 tttattgggt gatattttgt gttcagtgta attgtcttct ctttgctgat tatgttacca 3115 tggtactcct aaagcatatg cctcacctgg ttaaaaaaga acaaacatgt ttttgtgaaa 3175 gctactgaag tgccttggga aatgagaaag ttttaataag taaaatgatt ttttaaatat 3235 caaaaaaaaa aaaaaaa 3252 <210> SEQ ID NO 4 <211> LENGTH: 557 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Arg Asp Tyr Asp Glu Val Thr Ala Phe Leu Gly Glu Trp Gly Pro 1 5 10 15 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn 20 25 30 Gly Phe Thr Gly Leu Ser Ser Val Phe Leu Ile Ala Thr Pro Glu His 35 40 45 Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn 50 55 60 His Thr Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser 65 70 75 80 Cys Arg Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly 85 90 95 Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser 100 105 110 Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Ile 115 120 125 Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asp Trp Lys Ala Pro Leu 130 135 140 Thr Ile Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Ile Ser 145 150 155 160 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Val Thr 165 170 175 Met Gly Met Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Lys Asn 180 185 190 Phe Glu Met Phe Val Val Leu Phe Val Leu Val Gly Met Gly Gln Ile 195 200 205 Ser Asn Tyr Val Ala Ala Phe Val Leu Gly Thr Glu Ile Leu Gly Lys 210 215 220 Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Ile Phe Tyr Ala 225 230 235 240 Phe Gly Tyr Met Val Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp 245 250 255 Arg Met Leu Leu Val Ala Leu Thr Met Pro Gly Val Leu Cys Val Ala 260 265 270 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Gly 275 280 285 Arg Phe Glu Glu Ala Glu Val Ile Ile Arg Lys Ala Ala Lys Ala Asn 290 295 300 Gly Ile Val Val Pro Ser Thr Ile Phe Asp Pro Ser Glu Leu Gln Asp 305 310 315 320 Leu Ser Ser Lys Lys Gln Gln Ser His Asn Ile Leu Asp Leu Leu Arg 325 330 335 Thr Trp Asn Ile Arg Met Val Thr Ile Met Ser Ile Met Leu Trp Met 340 345 350 Thr Ile Ser Val Gly Tyr Phe Gly Leu Ser Leu Asp Thr Pro Asn Leu 355 360 365 His Gly Asp Ile Phe Val Asn Cys Phe Leu Ser Ala Met Val Glu Val 370 375 380 Pro Ala Tyr Val Leu Ala Trp Leu Leu Leu Gln Tyr Leu Pro Arg Arg 385 390 395 400 Tyr Ser Met Ala Thr Ala Leu Phe Leu Gly Gly Ser Val Leu Leu Phe 405 410 415 Met Gln Leu Val Pro Pro Asp Leu Tyr Tyr Leu Ala Thr Val Leu Val 420 425 430 Met Val Gly Lys Phe Gly Val Thr Ala Ala Phe Ser Met Val Tyr Val 435 440 445 Tyr Thr Ala Glu Leu Tyr Pro Thr Val Val Arg Asn Met Gly Val Gly 450 455 460 Val Ser Ser Thr Ala Ser Arg Leu Gly Ser Ile Leu Ser Pro Tyr Phe 465 470 475 480 Val Tyr Leu Gly Ala Tyr Asp Arg Phe Leu Pro Tyr Ile Leu Met Gly 485 490 495 Ser Leu Thr Ile Leu Thr Ala Ile Leu Thr Leu Phe Leu Pro Glu Ser 500 505 510 Phe Gly Thr Pro Leu Pro Asp Thr Ile Asp Gln Met Leu Arg Val Lys 515 520 525 Gly Met Lys His Arg Lys Thr Pro Ser His Thr Arg Met Leu Lys Asp 530 535 540 Gly Gln Glu Arg Pro Thr Ile Leu Lys Ser Thr Ala Phe 545 550 555 <210> SEQ ID NO 5 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5 ctgcacggaa ataactaatc tgtg 24 <210> SEQ ID NO 6 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 gagaggagct cgggttcaag 20 <210> SEQ ID NO 7 <211> LENGTH: 551 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 Met Arg Asp Tyr Asp Glu Val Ile Ala Phe Leu Gly Glu Trp Gly Pro 1 5 10 15 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn 20 25 30 Gly Phe Asn Gly Met Ser Val Val Phe Leu Ala Gly Thr Pro Glu His 35 40 45 Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn 50 55 60 Asn Ser Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser 65 70 75 80 Cys Ser Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly 85 90 95 Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser 100 105 110 Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Val 115 120 125 Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asn Trp Lys Val Pro Leu 130 135 140 Thr Thr Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Val Ser 145 150 155 160 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Ala Thr 165 170 175 Met Ala Val Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Ile Ser 180 185 190 Trp Glu Met Phe Thr Val Leu Phe Val Ile Val Gly Met Gly Gln Ile 195 200 205 Ser Asn Tyr Val Val Ala Phe Ile Leu Gly Thr Glu Ile Leu Gly Lys 210 215 220 Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Thr Phe Phe Ala 225 230 235 240 Val Gly Tyr Met Leu Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp 245 250 255 Arg Met Leu Leu Leu Ala Leu Thr Val Pro Gly Val Leu Cys Val Pro 260 265 270 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Arg 275 280 285 Arg Phe Arg Glu Ala Glu Asp Ile Ile Gln Lys Ala Ala Lys Met Asn 290 295 300 Asn Thr Ala Val Pro Ala Val Ile Phe Asp Ser Val Glu Glu Leu Asn 305 310 315 320 Pro Leu Lys Gln Gln Lys Ala Phe Ile Leu Asp Leu Phe Arg Thr Arg 325 330 335 Asn Ile Ala Ile Met Thr Ile Met Ser Leu Leu Leu Trp Met Leu Thr 340 345 350 Ser Val Gly Tyr Phe Ala Leu Ser Leu Asp Ala Pro Asn Leu His Gly 355 360 365 Asp Ala Tyr Leu Asn Cys Phe Leu Ser Ala Leu Ile Glu Ile Pro Ala 370 375 380 Tyr Ile Thr Ala Trp Leu Leu Leu Arg Thr Leu Pro Arg Arg Tyr Ile 385 390 395 400 Ile Ala Ala Val Leu Phe Trp Gly Gly Gly Val Leu Leu Phe Ile Gln 405 410 415 Leu Val Pro Val Asp Tyr Tyr Phe Leu Ser Ile Gly Leu Val Met Leu 420 425 430 Gly Lys Phe Gly Ile Thr Ser Ala Phe Ser Met Leu Tyr Val Phe Thr 435 440 445 Ala Glu Leu Tyr Pro Thr Leu Val Arg Asn Met Ala Val Gly Val Thr 450 455 460 Ser Thr Ala Ser Arg Val Gly Ser Ile Ile Ala Pro Tyr Phe Val Tyr 465 470 475 480 Leu Gly Ala Tyr Asn Arg Met Leu Pro Tyr Ile Val Met Gly Ser Leu 485 490 495 Thr Val Leu Ile Gly Ile Phe Thr Leu Phe Phe Pro Glu Ser Leu Gly 500 505 510 Met Thr Leu Pro Glu Thr Leu Glu Gln Met Gln Lys Val Lys Trp Phe 515 520 525 Arg Ser Gly Lys Lys Thr Arg Asp Ser Met Glu Thr Glu Glu Asn Pro 530 535 540 Lys Val Leu Ile Thr Ala Phe 545 550 <210> SEQ ID NO 8 <211> LENGTH: 614 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (184)..(184) <223> OTHER INFORMATION: n at 184 can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (323)..(323) <223> OTHER INFORMATION: n at 323 can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (506)..(506) <223> OTHER INFORMATION: n at 506 can be a or t or g or c <400> SEQUENCE: 8 gcggcccagg cccgcaacct tccctggtcg tgcgccatat gtaaggccag ccgcggcagg 60 accaaggcgg cggtgtcagc tckcgagcct accctccgcg gacggtcttg ggtckcctgc 120 tgcctggctt gcctggtcgg cggyrggtgc cccgcgcgca cgcgcaaagc ccgccgcgtt 180 cccngacccc aggccgcgct ctgtgggcct ctgagggcgg catgcgggac tacgacgagg 240 tgaccgcctt cctgggcgag tgggggccct tccagcgcct catcttcttc ctgctcagcg 300 ccagcatcat ccccaatggc ttnaccggcc tgtcctccgt gttcctgata gcgaccccgg 360 agcaccgctg ccgggtgccg gacgccgcga acctgagcag cgcctggcgc aaccacactg 420 tcccactgcg gctgcgggac ggccgcgagg tgccccacag ctgccgccgc taccggctcg 480 ccaccatcgc caacttctcg gcgctngggc tggagccggg gcgcgacgtg gacctggggc 540 agctggagca ggagagctgt ctggatggct gggagttcag tcaggacgtc tacctgtcca 600 ccattgtgac cggg 614 <210> SEQ ID NO 9 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 accatcgcca acttctcggc 20 <210> SEQ ID NO 10 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 ctttctgctg cttcagggga 20 <210> SEQ ID NO 11 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 ccatcgccaa cttctcgg 18 <210> SEQ ID NO 12 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 aatgttgtgg gactgctgct tc 22 <210> SEQ ID NO 13 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 gaagatcttg gaaggctcag gtgggagg 28 <210> SEQ ID NO 14 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 cgacgcgtgg cagcaggcga cccaagac 28 <210> SEQ ID NO 15 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 caggcccgga accttccctg gtcgt 25 <210> SEQ ID NO 16 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 acgaccaggg aaggttccgg gcctg 25 <210> SEQ ID NO 17 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 caggcccgca accttccctg gtcgt 25 <210> SEQ ID NO 18 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 acgaccaggg aaggttgcgg gcctg 25 <210> SEQ ID NO 19 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 tcggctggaa tattcccgac ctggcagccg a 31 <210> SEQ ID NO 20 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 tcggctgcca ggtcgggaat attccagccg a 31 <210> SEQ ID NO 21 <211> LENGTH: 39 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 gactgtcctg attggaatct tcaccctttt tttccctga 39 <210> SEQ ID NO 22 <211> LENGTH: 39 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 tcagggaaaa aaagggtgaa gattccaatc aggacagtc 39 <210> SEQ ID NO 23 <211> LENGTH: 400 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (385)..(385) <223> OTHER INFORMATION: n at residue 385 can be a or g or c or t <400> SEQUENCE: 23 gtcccgctgc cttcctaagc cgascccggg ctacctcggt cgtccccagc aggcgtggct 60 ggcagaggcc gggcctcgcc aggtccccag gacaggcccc gcccgggcct caggtgcact 120 cccggcccgc cccgcgccct cgcgtcccgc cccagctccg ccttcgccgg cgccgctctg 180 cctgccagcg gggcgcgcct tgcggcccag gcccgsaacc ttccctggtc gtgcgccata 240 tgtaaggcca gccgcggcag gaccaaggcg gcggtgtcag ctckcgagcc taccctccgc 300 ggacggtctt gggtckcctg ctgcctggct tgcctggtcg gcggyrggtg ccccgcgcgc 360 acgcgcaaag cccgccgcgt tcccngaccc caggccgcgc 400 <210> SEQ ID NO 24 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 taagccgagc ccgggcta 18 <210> SEQ ID NO 25 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 ccaggcccgg aaccttccc 19 <210> SEQ ID NO 26 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 cggcggtgtc agctcgcgag cctaccctcc gc 32 <210> SEQ ID NO 27 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 ggacggtctt gggtcgcctg ctgcctggct tg 32 <210> SEQ ID NO 28 <211> LENGTH: 32 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 cctggtcggc ggtaggtgcc ccgcgcgcac gc 32 <210> SEQ ID NO 29 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 gccaggttag gttccctttc 20 <210> SEQ ID NO 30 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 agcagcccaa attcttaaag g 21 <210> SEQ ID NO 31 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 gaatcacctc gctgcttttt 20 <210> SEQ ID NO 32 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 aaatgtggaa agggcatct 19 <210> SEQ ID NO 33 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 attaggcggt gtcaagagca 20 <210> SEQ ID NO 34 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 ggtcgtgcgc catatgtaag 20 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 gagaggagct cgggttcaag 20 <210> SEQ ID NO 36 <211> LENGTH: 136 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 36 gtgcttacaa cagaatgctg ccctacatcg tcatgggtag tctgactgtc ctgattggaa 60 tcytcaccct ttttttccct gaaagtttgg gaatgactct tccagaaacc ttagagcaga 120 tgcagaaagt gaaatg 136 <210> SEQ ID NO 37 <211> LENGTH: 2136 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (5)..(5) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7)..(7) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (229)..(229) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (324)..(324) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (325)..(325) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (326)..(326) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (327)..(327) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (328)..(328) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (330)..(330) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (331)..(331) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (334)..(334) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (569)..(569) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (593)..(593) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (617)..(617) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1063)..(1063) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1328)..(1328) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1767)..(1767) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2105)..(2105) <223> OTHER INFORMATION: n can be a or t or g or c <400> SEQUENCE: 37 ccccngnttc gcgccccaat ttctaacagc ctgcctgtcc cccgggaacg ttctaacatc 60 cttggggagc gccccagcta caagacactg tcctgagaac gctgtcatca cccgtagttg 120 caagtttcgg agcggcagtg ggaagcatgc gggactacga cgaggtgatc gccttcctgg 180 gcgagtgggg gcccttccag cgcctcatct tcttcctgct cagcgccanc atcatcccca 240 atggcttcaa tggtatgtca gtcgtgttcc tggcggggac cccggagcac cgctgtcgag 300 tgccggacgc cgcgaacctg agcnnnnncn ngcngaacaa cagtgtcccg ctgcggctgc 360 gggacggccg cgaggtgccc cacagctgca gccgctaccg gctcgccacc atcgccaact 420 tctcggcgct cgggctggag ccggggcgcg acgtggacct ggggcagctg gagcaggaga 480 gctgcctgga tggctgggag ttcagccagg acgtctacct gtccaccgtc gtgaccgagt 540 ggaatctggt gtgtgaggac aactggaang tgcccctcac cacctccctg ttnttcgtag 600 gcgtgctcct cggctcnttc gtgtccgggc agctgtcaga caggtttggc aggaagaacg 660 ttctcttcgc aaccatggct gtacagactg gcttcagctt cctgcagatt ttctccatca 720 gctgggagat gttcactgtg ttatttgtca tcgtgggcat gggccagatc tccaactatg 780 tggtagcctt catactagga acagaaattc ttggcaagtc agttcgtatt atattctcta 840 cattaggagt gtgcacattt tttgcagttg gctatatgct gctgccactg tttgcttact 900 tcatcagaga ctggcggatg ctgctgctgg cgctgacggt gccgggagtg ctgtgtgtcc 960 cgctgtggtg gttcattcct gaatctcccc gatggctgat atcccagaga agatttagag 1020 aggctgaaga tatcatccaa aaagctgcaa aaatgaacaa canagctgta ccagcagtga 1080 tatttgattc tgtggaggag ctaaatcccc tgaagcagca gaaagctttc attctggacc 1140 tgttcaggac tcggaatatt gccataatga ccattatgtc tttgctgcta tggatgctga 1200 cctcagtggg ttactttgct ctgtctctgg atgctcctaa tttacatgga gatgcctacc 1260 tgaactgttt cctctctgcc ttgattgaaa ttccagctta cattacagcc tggctgctat 1320 tgcgaacnct gcccaggcgt tatatcatag ctgcagtact gttctgggga ggaggtgtgc 1380 ttctcttcat tcaactggta cctgtggatt attacttctt atccattggt ctggtcatgc 1440 tgggaaaatt tgggatcacc tctgctttct ccatgctgta tgtcttcact gctgagctct 1500 acccaaccct ggtcaggaac atggcggtgg gggtcacatc cacggcctcc agagtgggca 1560 gcatcattgc cccctacttt gtttacctcg gtgcttacaa cagaatgctg ccctacatcg 1620 tcatgggtag tctgactgtc ctgattggaa tcytcaccct ttttttccct gaaagtttgg 1680 gaatgactct tccagaaacc ttagagcaga tgcagaaagt gaaatggttc agatctggga 1740 aaaaaacaag agactcaatg gagacanaag aaaatcccaa ggttctaata actgcattct 1800 gaaaaaatat ctaccccatt tggtgaagtg aaaaacacaa aaataagacc ctgtggagaa 1860 attcgttgtt cccactgaaa tggactgact gtaacgattg acaccaaaat gaaccttgct 1920 atcaagaaat gctcgtcata cagtaaactc tggatgattc ttccagataa tgtccttgct 1980 ttacaaacca accatttcta gagagtctcc ttactcatta attcaatgaa atggattggt 2040 aagatgtctt gaaaacatgt tagtcaagga ctggtaaaat acatataaag attaacactc 2100 atttnccaat catacaaata ctatccaaat aaaaat 2136 <210> SEQ ID NO 38 <211> LENGTH: 551 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 Met Arg Asp Tyr Asp Glu Val Ile Ala Phe Leu Gly Glu Trp Gly Pro 1 5 10 15 Phe Gln Arg Leu Ile Phe Phe Leu Leu Ser Ala Ser Ile Ile Pro Asn 20 25 30 Gly Phe Asn Gly Met Ser Val Val Phe Leu Ala Gly Thr Pro Glu His 35 40 45 Arg Cys Arg Val Pro Asp Ala Ala Asn Leu Ser Ser Ala Trp Arg Asn 50 55 60 Asn Ser Val Pro Leu Arg Leu Arg Asp Gly Arg Glu Val Pro His Ser 65 70 75 80 Cys Ser Arg Tyr Arg Leu Ala Thr Ile Ala Asn Phe Ser Ala Leu Gly 85 90 95 Leu Glu Pro Gly Arg Asp Val Asp Leu Gly Gln Leu Glu Gln Glu Ser 100 105 110 Cys Leu Asp Gly Trp Glu Phe Ser Gln Asp Val Tyr Leu Ser Thr Val 115 120 125 Val Thr Glu Trp Asn Leu Val Cys Glu Asp Asn Trp Lys Val Pro Leu 130 135 140 Thr Thr Ser Leu Phe Phe Val Gly Val Leu Leu Gly Ser Phe Val Ser 145 150 155 160 Gly Gln Leu Ser Asp Arg Phe Gly Arg Lys Asn Val Leu Phe Ala Thr 165 170 175 Met Ala Val Gln Thr Gly Phe Ser Phe Leu Gln Ile Phe Ser Ile Ser 180 185 190 Trp Glu Met Phe Thr Val Leu Phe Val Ile Val Gly Met Gly Gln Ile 195 200 205 Ser Asn Tyr Val Val Ala Phe Ile Leu Gly Thr Glu Ile Leu Gly Lys 210 215 220 Ser Val Arg Ile Ile Phe Ser Thr Leu Gly Val Cys Thr Phe Phe Ala 225 230 235 240 Val Gly Tyr Met Leu Leu Pro Leu Phe Ala Tyr Phe Ile Arg Asp Trp 245 250 255 Arg Met Leu Leu Leu Ala Leu Thr Val Pro Gly Val Leu Cys Val Pro 260 265 270 Leu Trp Trp Phe Ile Pro Glu Ser Pro Arg Trp Leu Ile Ser Gln Arg 275 280 285 Arg Phe Arg Glu Ala Glu Asp Ile Ile Gln Lys Ala Ala Lys Met Asn 290 295 300 Asn Thr Ala Val Pro Ala Val Ile Phe Asp Ser Val Glu Glu Leu Asn 305 310 315 320 Pro Leu Lys Gln Gln Lys Ala Phe Ile Leu Asp Leu Phe Arg Thr Arg 325 330 335 Asn Ile Ala Ile Met Thr Ile Met Ser Leu Leu Leu Trp Met Leu Thr 340 345 350 Ser Val Gly Tyr Phe Ala Leu Ser Leu Asp Ala Pro Asn Leu His Gly 355 360 365 Asp Ala Tyr Leu Asn Cys Phe Leu Ser Ala Leu Ile Glu Ile Pro Ala 370 375 380 Tyr Ile Thr Ala Trp Leu Leu Leu Arg Thr Leu Pro Arg Arg Tyr Ile 385 390 395 400 Ile Ala Ala Val Leu Phe Trp Gly Gly Gly Val Leu Leu Phe Ile Gln 405 410 415 Leu Val Pro Val Asp Tyr Tyr Phe Leu Ser Ile Gly Leu Val Met Leu 420 425 430 Gly Lys Phe Gly Ile Thr Ser Ala Phe Ser Met Leu Tyr Val Phe Thr 435 440 445 Ala Glu Leu Tyr Pro Thr Leu Val Arg Asn Met Ala Val Gly Val Thr 450 455 460 Ser Thr Ala Ser Arg Val Gly Ser Ile Ile Ala Pro Tyr Phe Val Tyr 465 470 475 480 Leu Gly Ala Tyr Asn Arg Met Leu Pro Tyr Ile Val Met Gly Ser Leu 485 490 495 Thr Val Leu Ile Gly Ile Leu Thr Leu Phe Phe Pro Glu Ser Leu Gly 500 505 510 Met Thr Leu Pro Glu Thr Leu Glu Gln Met Gln Lys Val Lys Trp Phe 515 520 525 Arg Ser Gly Lys Lys Thr Arg Asp Ser Met Glu Thr Glu Glu Asn Pro 530 535 540 Lys Val Leu Ile Thr Ala Phe 545 550 <210> SEQ ID NO 39 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 gtgcccagag agtcctccta 20 <210> SEQ ID NO 40 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 ttctccctaa ggcattttgg t 21 <210> SEQ ID NO 41 <211> LENGTH: 26850 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (49)..(49) <223> OTHER INFORMATION: n at 49 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (134)..(134) <223> OTHER INFORMATION: n at 134 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (546)..(546) <223> OTHER INFORMATION: n at 546 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (877)..(877) <223> OTHER INFORMATION: n at 877 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1338)..(1338) <223> OTHER INFORMATION: n at 1338 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1985)..(1985) <223> OTHER INFORMATION: n at 1985 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2124)..(2124) <223> OTHER INFORMATION: n at 2124 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2307)..(2307) <223> OTHER INFORMATION: n at 2307 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3115)..(3115) <223> OTHER INFORMATION: n at 3115 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3159)..(3159) <223> OTHER INFORMATION: n at 3159 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3191)..(3191) <223> OTHER INFORMATION: n at 3191can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3282)..(3282) <223> OTHER INFORMATION: n at 3282 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3661)..(3661) <223> OTHER INFORMATION: n at 3661 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3748)..(3748) <223> OTHER INFORMATION: n at 3748 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3797)..(3797) <223> OTHER INFORMATION: n at 3797 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3905)..(3905) <223> OTHER INFORMATION: n at 3905 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4260)..(4260) <223> OTHER INFORMATION: n at 4260 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4903)..(4903) <223> OTHER INFORMATION: n at 4903 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (5971)..(5971) <223> OTHER INFORMATION: n at 5971 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6111)..(6111) <223> OTHER INFORMATION: n at 6111 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6148)..(6148) <223> OTHER INFORMATION: n at 6148 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6400)..(6400) <223> OTHER INFORMATION: n at 6400 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6468)..(6468) <223> OTHER INFORMATION: n at 6468 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6575)..(6575) <223> OTHER INFORMATION: n at 6575 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7287)..(7287) <223> OTHER INFORMATION: n at 7287can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (8495)..(8495) <223> OTHER INFORMATION: n at 8495 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9918)..(9918) <223> OTHER INFORMATION: n at 9918 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9919)..(9919) <223> OTHER INFORMATION: n at 9919 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9924)..(9924) <223> OTHER INFORMATION: n at 9924 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9947)..(9947) <223> OTHER INFORMATION: n at 9947 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10143)..(10143) <223> OTHER INFORMATION: n at 10143 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10357)..(10357) <223> OTHER INFORMATION: n at 10357 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10379)..(10379) <223> OTHER INFORMATION: n at 10379 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10384)..(10384) <223> OTHER INFORMATION: n at 10384 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10580)..(10580) <223> OTHER INFORMATION: n at 10580 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10717)..(10717) <223> OTHER INFORMATION: n at 10717 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10718)..(10718) <223> OTHER INFORMATION: n at 10718 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10719)..(10719) <223> OTHER INFORMATION: n at 10719 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10781)..(10781) <223> OTHER INFORMATION: n at 10781 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11111)..(11111) <223> OTHER INFORMATION: n at 11111 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11150)..(11150) <223> OTHER INFORMATION: n at 11150 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11211)..(11211) <223> OTHER INFORMATION: n at 11211 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11383)..(11383) <223> OTHER INFORMATION: n at 11383 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11489)..(11489) <223> OTHER INFORMATION: n at 11489 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11502)..(11502) <223> OTHER INFORMATION: n at 11502 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11503)..(11503) <223> OTHER INFORMATION: n at 11503 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11515)..(11515) <223> OTHER INFORMATION: n at 11515 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11640)..(11640) <223> OTHER INFORMATION: n at 11640 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11937)..(11937) <223> OTHER INFORMATION: n at 11937 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (13423)..(13423) <223> OTHER INFORMATION: n at 13423 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (14232)..(14232) <223> OTHER INFORMATION: n at 14232 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (14579)..(14579) <223> OTHER INFORMATION: n at 14579 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (15503)..(15503) <223> OTHER INFORMATION: n at 15503 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (15601)..(15601) <223> OTHER INFORMATION: n at 15601 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (15755)..(15755) <223> OTHER INFORMATION: n at 15755 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (15823)..(15823) <223> OTHER INFORMATION: n at 15823 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (16062)..(16062) <223> OTHER INFORMATION: n at 16062 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (16204)..(16204) <223> OTHER INFORMATION: n at 16204 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (16635)..(16635) <223> OTHER INFORMATION: n at 16635 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (16637)..(16637) <223> OTHER INFORMATION: n at 16637 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (16724)..(16724) <223> OTHER INFORMATION: n at 16724 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (17546)..(17546) <223> OTHER INFORMATION: n at 17546 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (18232)..(18232) <223> OTHER INFORMATION: n at 18232 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (18260)..(18260) <223> OTHER INFORMATION: n at 18260 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (18414)..(18414) <223> OTHER INFORMATION: n at 18414 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (18418)..(18418) <223> OTHER INFORMATION: n at 18418 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (18424)..(18424) <223> OTHER INFORMATION: n at 18424 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (20789)..(20789) <223> OTHER INFORMATION: n at 20789 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (21317)..(21317) <223> OTHER INFORMATION: n at 21317 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (21696)..(21696) <223> OTHER INFORMATION: n at 21696 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (22199)..(22199) <223> OTHER INFORMATION: n at 22199 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (23399)..(23399) <223> OTHER INFORMATION: n at 23399 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (23712)..(23712) <223> OTHER INFORMATION: n at 23712 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (27712)..(27712) <223> OTHER INFORMATION: n at 27712 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (24038)..(24038) <223> OTHER INFORMATION: n at 24038 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (24565)..(24565) <223> OTHER INFORMATION: n at 24565 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (25073)..(25073) <223> OTHER INFORMATION: n at 25073 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (25419)..(25419) <223> OTHER INFORMATION: n at 25419 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (25420)..(25420) <223> OTHER INFORMATION: n at 25420 can be a or g or c or t <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (25426)..(25426) <223> OTHER INFORMATION: n at 25426 can be a or g or c or t <400> SEQUENCE: 41 taattttttt aagtctatta tgctttatgc aaatgtttag atttccttnt taaaaatctg 60 ctggccaggt taggttccct ttctgtagct ttattttcaa ctcataatat agtgactatt 120 aaatattctt tacncaacac attatattgt aaaaatatac acttagttct gtttctatca 180 ctaagccact actattttaa aaaggaatat cttgcattgt taagtttagc agcccaaatt 240 cttaaaggcc ttaggaatgg tgctgtccaa taagataacc aatagctaca tgtggctact 300 gagcacttaa aaaatgagtc tggccaggca tagtggctca cgtctgtaat tcagcatttt 360 gggaggctga ggtgggagga ttgcttaaac ccaggagtct gagaccagcc tgggcaacac 420 agggatgcct tgtctctgta aaataaaaaa aataaaaaaa ttagctgggc acggtggcat 480 gtgcctgtag tcctagctac tcagcaggct gaggcaggag gcccacttaa gcttaggagt 540 tcaggnctgc ggtgagctat gattgtgcca ctgcactcta gcctgggtga cacagtggga 600 ccgtgtctcc aataaataaa tgaataaata aatattaaaa aataaaaagt gtggctagtc 660 caaattgaaa tgtgctgtaa aatacacact ggattccttt tttttttttt ttcaaatcct 720 gagaacctgt gaaacacact gaattcttaa gatttagtat gaggagggga aaaaaagatc 780 aatgatttac atataacaat gtaaaatatc aataatttct atattgatta tatgatgaaa 840 tgatcatgtt ctggatatac ttgattaaat ataccantaa agttaatttc atcttttatt 900 tttacttttt aaatatgcag cattgcccaa taaaatacag gacaaccagt tacattttta 960 ttttatatat tcctgcttgg gacataatat ttaaaaatta ttcattctat atctgaaatt 1020 caaatttaac taggagtcct atatttttat ttgctaaatc tggcaatttt attaatatgg 1080 ctactagaaa agttaacata acaaatgtag ctccttatcc tatggaacat tgctgcttta 1140 gaatcacctc gctgcttttt ttttttttcc agttagcttc tgaataaact ctgcacggaa 1200 ataactaatc tgtggggaat atttaaccct aggctaggat cgttaatcgt gaagttaaat 1260 ttttacatct gcatgaacaa aatggcttgt tacagacgaa aatgtggaaa gggcatctgg 1320 actagaatga aaagtcanag ctcccagcct ctctactagg gtagttaaca gtcccaggtt 1380 caaaataatc cccgtccctc ttataagatt aggcggtgtc aagagcaact atctgtgaga 1440 ccctgggcca gtgactttct ccttacctcc gcccccaagt aggccttgca aaaagctggg 1500 aggggtgcgt tttcaacact ggagcttcgc ggccgctctc ccactcgctc cccgcccggc 1560 gctagaggag cgagttcgga ctcggacccc aaggcctcga gtcccgctgc cttcctaagc 1620 cgaccccggg ctacctcggt cgtccccagc aggcgtggct ggcagaggcc gggcctcgcc 1680 aggtccccag gacaggcccc gcccgggcct caggtgcact cccggcccgc cccgcgccct 1740 cgcgtcccgc cccagctccg ccttcgccgg cgccgctctg cctgccagcg gggcgcgcct 1800 tgcggcccag gcccggaacc ttccctggtc gtgcgccata tgtaaggcca gccgcggcag 1860 gaccaaggcg gcggtgtcag ctckcgagcc taccctccgc ggacggtctt gggtckcctg 1920 ctgcctggct tgcctggtcg gcggyrggtg ccccgcgcgc acgcgcaaag cccgccgcgt 1980 tcccngaccc caggccgcgc tctgtgggcc tctgagggcg gcatgcggga ctacgacgag 2040 gtgaccgcct tcctgggcga gtgggggccc ttccagcgcc tcatcttctt cctgctcagc 2100 gccagcatca tccccaatgg cttnaccggc ctgtcctccg tgttcctgat agcgaccccg 2160 gagcaccgct gccgggtgcc ggacgccgcg aacctgagca gcgcctggcg caaccacact 2220 gtcccactgc ggctgcggga cggccgcgag gtgccccaca gctgccgccg ctaccggctc 2280 gccaccatcg ccaacttctc ggcgctnggg ctggagccgg ggcgcgacgt ggacctgggg 2340 cagctggagc aggagagctg tctggatggc tgggagttca gtcaggacgt ctacctgtcc 2400 accattgtga ccggggtggg tgccggcccc tgctggggct gagaccaggg ctcggaggac 2460 ctgtcgcggt ccttgaaccc gagctcctct ctcccagatg cgcactggac gctgtcactc 2520 cccctccccc aacggtcaac accctagcga tggagaccct ccagccaggt ggcttgggaa 2580 cgcttcacga ggtgacctcc agccacagtg tgctcctccc tgcacaggtg gtcagtctgg 2640 cctcccgtcc tgatggccac tttgaagagg gtaccaggaa ggtcctggcg gtccctgggc 2700 gatgctctat ggccctgtgt gtccaggact tactctagtt ggggttgggg gtggtaagta 2760 gcagagccag gacttgggcc aggggctatc ccgtttttcc tctagtctct tgatttcttt 2820 ttagaagaga agaaatactt ctctttcctg aacttttaaa agttaaataa agcatgtgta 2880 tacaactgcc tcttcccttt ttcctctagt tactccttcc cctaccgtcc acaacccaaa 2940 aacgacaatc tggtcatgcc ctgtaagtaa ttgtttgcct tttcccatgg tcagttgtca 3000 gtcttttttt tttttttttt tttttgagac agagtctccc tctgtcacca ggctggagcg 3060 cagtcgtgtg ttcttggctc actgcaacct tcgcagtcgt gcgttcttgg ctcantgcaa 3120 tcttcgcctt ccgggctcaa gtgattctcc tgcctcagnc tccgagtagc tgtgagccac 3180 gacgcccagc naatttttgt gtttttagta gagacggggt ttcaccgtgt tggccaggat 3240 ggtctcgatc tcttgacctc gtgatctgcc tgcttctgcc tncaaagctg ggattacaac 3300 cgtgagccac cacgccaggc cgtcagttgt cactctttaa gatccattca tctgaagatg 3360 ggttcagggt gacttgttga cctggaatat tttctcaggt attatgaggc aaggctgtcg 3420 gccagattta gttaaagcat acagccttag gtcatagggt gtgggggagc ctttctcatt 3480 tctcatcccc ttggattttc cctctgggtg gttttgtctg tcccctccga acctgttgga 3540 gcagttgttg gagctggatg taggaacatg atgttaatga tgtatgtgtt ttgtgtcttt 3600 tttagacact ggcactctag ctccctgaag tttcagcagc attgagtaag tagccagtga 3660 ntagccctca ttgatagata ggctcactaa atgtgcagat gaccaattcg caggttagag 3720 aaggcttccc agaagaggag gcctctcngt gagcctaggg tgttcagctc agcataatag 3780 tgagctgaag gccccantgc agcagcaaga aaccacccag caggacggcg gagttcacag 3840 agaggggaga gttcatagag agggagagtg ccacaggccc tggcacagct tcaagccctg 3900 ctggntgttg gtgctgagcc tcccctcctg gagcctcaga ggggcttaca ggggctctgg 3960 agatcccaac tgtgttgctt cttggcgtca tcacccttca atggagtctg agagctaccc 4020 tgggagatcc aagtgtgtgt gcatgtgtgt gttttttctt tttggaaatt tgatgtcccc 4080 agcatttgga cctgctttct ccacatatat gtagtgggag tgtgaccgga gccccactgg 4140 gatttcttag ctagtgacat agcttcagtg tccagaggca tcatggcttg acaaaagagg 4200 cactccttgg aggtagccaa ctgtgctttc tggcccatga atccacagga aattggaacn 4260 ttcagttgcc acaaatcctg ggtcctagcc tcacaggtgg gtgtgttacc ttcccggaag 4320 ccagtgagta ctatgaaagc agaggctgtc cctgaggttg caggcagagg ccacagaggg 4380 gaacatgaca caggaatccc tacaaattct acttggggct gcctaaagaa gagggaagta 4440 gtgaagcaag aagaagcaca tggcatctct tggagtttta cattgacccc tgagggttcc 4500 ccggcttact ctagtcactt gttcctgctt tgctgcctcc atcccacatt gggctgagtg 4560 atggtggcat tgatgagctc ccaaaggcca gctgtgccag ggggtctgac cttatcttgc 4620 tgccaatgtc agccttttgt tttttaatat ttagactatt tatttagctg tcttagcagt 4680 ttcaaaggag ttatgtgccc tttcacctac ttatatgttg tcagtctttg cagggaggcc 4740 agattaatgc ttagatcttt gttttgggct actggaatgc ttgacttgaa gttcagagct 4800 gcttgttccc aggtgaacag ctactgctgg aagttgctgc atcaacattc taatggcttt 4860 ttctatggcc tgttgtcttt caacccaaac ctggcctgct gancactgca tctagtccca 4920 tgcctgctaa atgtctctaa gcctgccctc tgccccaaat catacataaa ggtgtttgta 4980 agtacactgg tattgaatta ctagtcatat tttttccact gaagactgga acctcaggtg 5040 tcctgtttgg atttttttaa tttgttcaag ttaaagtaca tacatgtagt accaaacttt 5100 gtggtggatt tagatctttg cgtcttcctc aatttctgac acaattctgg atgcagaggg 5160 aggttctcag gaaaattttt attgaatgag ttaatgaata atttaagaaa tcatctctaa 5220 agtttgagaa ctaaagaaaa atagttcagt tcttagaagg gaaacttgag ggtggctgaa 5280 aaggattgac tggaattttt taaaggaaat gtgactcccc ctgcccactg actggggctt 5340 tgatgccaca tggatgtgga atgaggtgtt gggattggca gagggaatct gctagcaatt 5400 aataaataaa taaatattgg cagggcgtgg tggctcacgc ctgtaatccc agcactttgg 5460 gaagccaagg cagcaggtca cttgaggtcg ggagttcaag accagtctgg ccaacatggt 5520 gaaactccat ctctactaaa aatacaaaaa ttagctgggt gtggtggcac atgcctgtat 5580 tcccagctac ttgggagact gaagcaggag aatcgcttga acccaggagg cgggctttgc 5640 agtgaaccga gatcgagcct ctgcactcta gcctgggcga caaagcgaga ctccatctca 5700 aaagaataat aataatatta ataaataaaa atgatttatg aggtaaaaga gttttatgcc 5760 cccatgttcc aggaatagtt tggtggtcca catggttctc ggctggcctc tcctctggcc 5820 cctcagtcat ccctggggta ctggggaatt agccaaccca tcatgcagtg cttcttggcc 5880 atggactgcc ccatctgctg gaaacctggg ttgtttctga ggttgtctgg gctgtccgct 5940 ctttggtttc accatagctc tgtccagcct ntggacagac aggttccttg agaaacttcc 6000 ggctgggtgt ggtggctcat gcctgtaaac ccagcacttt gggaggctga ggcaggtgga 6060 tcacaaggca ggagttcgag accagcctgg ccaacatggt gaaacctcgt ntccgctaaa 6120 aatacaaaaa ttagccctgc gtggtggngg gtgcctgtaa tcccagctac tcgggaggga 6180 ggctgaggca ggagaatttc ttgaacctgg gaagtggggg ttgcagtagc caagatcgca 6240 ccattgcatg ccagcctggg tgacaagagc aagactccgt ctcaaaaaaa aaaaaagaaa 6300 aagaaaagaa acttccaagc tgctctgcat cgccttgctc tccacctgtc tgcttctaag 6360 aagccctcgg cccagtcctg ggtgggactc ccactccctn cccattgtcc tggactagct 6420 tttctatcag ccttatcttg tgtagagaca gatagtctta gaagatgnga gagccctcac 6480 tgttatcccc aaagctgcct ggaggaaaag ccagagcaac ctgggagctg ggaccggggc 6540 tgactctggg cagcagagac ccgagagacc tggancttga acctcactgt tacgcctttg 6600 ttgatttctc tcactcaggg gacacacaga ccctcatcca gccttttgca gctatatggc 6660 aaggcagaga agccacttgc ggggtcccgt ggcccactat gcacgtacat agtagacaca 6720 tctggccatg agtggtcaga ttgagccact ctctagctag ctgacacctg tcatcctggg 6780 tcaaatttct gacagttgac acaaagcagg gggtcaggga gccaaaaaaa aaaatggcca 6840 ggtgtggtgg ctcttgcctg taatcccagg gctttgggag gccaaggtgg gcagataacc 6900 tgaggtcaga gttcaagacc agcctggtca acatggcaaa accccgtctc tactaaaaat 6960 acaaaaatta gccaggctgg tggtgcatcc ctgtagtccc agccactcag gaggctgagg 7020 catgagaatc acttgaaccc gggaggtgga ggttgcagtg agccgagatt gtgccactgc 7080 actccagcct gggagacaga gcaagactct gtttcaaaag aaaaaaaaga gtattctgga 7140 gattgaagtt caggagttca gggttcatct cgactttggg cagccaagca agaactaaag 7200 tataccaaga tgttgaaggt tgataccttt ttatttatcg attcattcac tcacctatgt 7260 accaaagagc tcctgagcct ctcttcnata cagggggcac tgccaggagt tgtagaggat 7320 gtgatagcaa agataggaaa taccttttct ctttgctctg acaacggtgg ggcaaggatt 7380 catcattgat ttcagcagga ggcaggataa aatgtgtgta ggaatatagg aatacatggc 7440 aatcagtaac atgtggtacc tagcagcatg tctgactgtt gatacggtca ggctaggtac 7500 atcccctcag ggaagaactt ctgtcttagg ggcacacacc ctatcttttt tcccttcctg 7560 ccaattcaca ggtaagaaca tttagtccca gggaactatg tcatctctct acttctcata 7620 actgaaaaag cagtgccaat tatgtatgag gtataggaga cacaattctc cctcttttta 7680 aaaatgttta atagctttat taaggtgtaa atgacataaa aactgcatgt agctaaagca 7740 tgcaatttgg cacacatgta tctctacacc cttgaaacca tcaccactag aaaggtgcat 7800 ttctccccag gaagaggggc aagtctaggc cctttgccag agttgctccc agattgtttt 7860 caggttgggc ctgcattcac agctcagcca gctgaagggt gacagcatta gactcgtgac 7920 ccaaatctta aacccacaca ttccatttta acattgatac ctgtgatcat cagccagtat 7980 agcccatccc atgtgccagg cggaggcatc aataagctgg tctgtagcag ctttaatcac 8040 agctggggag ccaggagcta aggaatgcta gactcctttg taaacaattt aagtaggggg 8100 tacttagcct ggactctatg tgcttctcat ccacctcttc tcagggagat tctggccaag 8160 tcctggaacc tactgcagtc catctggtgg ttgacagata tgtggacgga ttggcaggct 8220 gggacccaat ctatgtttgc ccttgtgttc agttttgaga cctagcacct ttcctgatcc 8280 tgctcacaga ccccctgcgg ccaataggaa agaagtgtta atgcatattt gcttttggag 8340 ggcccaaagc caggcccaga gagttgtcaa gggcggtcag tggtgggtgg atggcagagt 8400 taaccaagga gttacacacc tgcctagact aaggacaggc tggaccaagt agagagggtg 8460 gggctaaggg agcctgagag atgctctggg gcctntctca aaatgagcac tatagtcacc 8520 ctgtcccctg cagagattgt ctgacctggt tttaggtcac acccaacctt gccagccaag 8580 gagtctttag aagcctgata ttgggagacc tgtcctgggg tctacaaccc cagaactcac 8640 tgcagaagcc cacgtggatt gctagtctag ctcagccata tgggtcccca accctcacct 8700 catgatagtc ctgtgagaaa ccgctgctga ccctttgttc atgttttcat cttttccact 8760 ataaaagaca tgctagctgg gaaatagagc ccatcatact caagagtggc aggagccagg 8820 tcctggcccc tgaagcttgg cctcacacac agaggccggc accctgtcat caattccctc 8880 agctttttct ccgcctccac tcccagtcct agatttagca gccatgtgtg ggtgggggcc 8940 actgcaggga tacttaccca cctaccagag agatggcctg tgggtgctgg cccttctgag 9000 gctgtggagg ttggaggctg tggcagcctg ggcagtcagg ctgtggtcct cccatgttct 9060 tgactcctgc tagtctgggc tgcctcctga ttaggggttg gatgctccag ttcttccctg 9120 ggttggggat tgccacccta ctcccagccc atccaggttc acgcttattc caaagcggag 9180 caccagcagt gtgcctgctg cgggagttct ccgtgtccag cctgagggtt gcctgccaac 9240 ccctctgaga ggtgcccgga ggctgtgcgc ccacactgcc cagcagtgcg gagaagcagg 9300 cttgtttttc cctgtcactg gcttggaaga gatgctttgt tctagggagc cgcatgtccc 9360 cttgcctgcg ttgttggtga ggagccagca ggctccgtgg agggcaggct agcagcctgg 9420 caccagggag gcaagggtct gagttcctag gagggtggtt gctcatgtga gaagtctgca 9480 aaggttacta ctgagcacca tctctctgtc tgaaaaacat ttttcatttt tctgtgaacc 9540 actaagtttc ccgtttgggc tttcttcctg cttttggctc ttgtttaggc aggcgtagcc 9600 agatccaagc gtctggctgc ttccccatgt cttcagacct ctttttctgt tcatggtaac 9660 tatagatgga accacacatt ggaagctgga aactcaagcg gtgcagccta ttccttaccc 9720 caatccctgt tttacaaatg gggaaatcaa ggcacagcat ggggtgatgc ttatctgagg 9780 ttggaagagt taatagtaga gtgggagcta aaacccagtt tcttacctcc aagctcaggg 9840 ctttcagctg taattgagcc tagtatagtt ggtgtgcagc atcagggatt ccagctctaa 9900 aggtcacaaa aaggaccnng gggntcattg gcccagggtg ggaaccngag cagagcaggt 9960 ccagatggtg cactctgtgc cctggcctta gtttcttgct ggatgctttg gcccgtagag 10020 ccccagagcc ctgcttccag aaccactcca gtgacgttca tgccaatggc ctgaacccca 10080 ctgagcgagg gtgccctgcc tcttccacag ccctgggctc cgctcagatt tttaggagca 10140 agngttagag gccttgcttt ctccagggtc agcatgtgga cagaacactt actctctgcc 10200 tgtctctcct cctcaaaatg gaagcaagac agtggggcct acaatgctat gaaaaacagg 10260 atgggaaaga agcctgctct ctgccttcct gcccaggtga gccatcacct gactaagtga 10320 gttcacactc agagcgtgtg gggatggcag gatgttntga cttcattttc caggatgcnt 10380 ttgntttaaa accttttaaa aagaagtgaa tgatacaccc cctttgctca tcttgcagtg 10440 gaacctggtg tgtgaggacg actggaaggc cccactcaca atctccttgt tcttcgtggg 10500 tgtgctgttg ggctccttca tttcagggca gctgtcagac aggtaaggtg tctgtcttct 10560 ggagcaccag gggacctcan cactgaggaa gaagcgtgtg cctggccctt gatttcagtt 10620 ggtagtattc tgtcagcgca gggccctgta ttttaaagaa gaggaagcta tgtctgtgat 10680 atagactcca tgcctagtaa gaagagccaa caaatcnnnt gactccgtaa ttcttgctaa 10740 gtaaagaaac ctgagctgtc taagctgaat gtatctgtga nccggttgac taggtaatat 10800 gccatgattc acttctgcag tagcctggct tgcctcccct gggtcactgt gactctgtca 10860 tgcccctgag catgggagag gttgacatca tgcacacatg cacatgtgct agattgtaga 10920 tctgtagtag tgccacggtg tctgcctctg tagtcccaag aagaccagca ttctctctgc 10980 aaagtgaaag gagctctcac cagccactag tggtatgaaa agcagaactc ttttgtccac 11040 aaggctgatg ccccttagct aagtggcctg tggttttggc atttacttta tgacaggagg 11100 gagaatagtg ntttgatcca tttcttataa gcaggttatt tgtataattn taaagctttt 11160 aactcaagga aacattaacg gcttagagaa tcccaaaccc ctcgaaatta natgcacaat 11220 gttagagact acatgtgagc atttttttgg agagaggtcc gtagctttca tgaagttctt 11280 agaggggtcc attatgttgt gtcttctttc cctggagctt cagggtctgt cagagaagac 11340 tgtgaagaga gtagcagcct tcagcaagtc cttggccaca tgncacatgt gagaacaccc 11400 cacaaatcgg tgggttagcc ggtggaaagg agtcccagca tcttccctgg tttttaattc 11460 ctggcctcaa gcaatcctcc ctccataanc tcccaaagtg cnnggattac aggcntgaga 11520 caccatgcgc agccagatat tttttattgt tgttgttttt ttttggaaaa ggagtttcac 11580 tcttgttacc caggctggag tgcaatggca cgatctcggc tcactgcaac ctctgcctcn 11640 caggttcaag agattctcct gtctcagcct cctgagttgc tgggattaca ggcatgcacc 11700 accatgccca gctaattttg tatttttaat agagacaagg tttctccatg ttggtcaggc 11760 tggtctcaaa ctcccgacct caggtgatcc acccacctcg gcctcccaaa gtgctgggat 11820 tacaggcgcg agccactgca cctgcccagc cagatttttt tttaaaaagc aggttaacct 11880 gtttattatt cctactttac agatggagaa agtgagacag agggattaaa taacttnccc 11940 aaggtttcac agctggcaag tggcagagtt aggatttgga cccaggtagt cttgctcctc 12000 tattgtgtat ggactactgt tctaggtccc tgctgtccta aaacttgctt tctagcaagg 12060 tggaatgtat taaacaacca agtgaggaag tcgttgttgt ccttggccat ggtaagagat 12120 acagagaagt gcagggtgcc acaggagtgt ctaacagagg aggtcagggg cagcatccct 12180 gagaaggtga agcatgagcg agagtgggaa gatgagtcga aagtagccag ctgaggggta 12240 gagaggagaa agaacatcca ggcagggaga atagcaagtg ctaaagccgg ggctcatgaa 12300 aaggcatggg agcaggacaa agtccgtgtg gtagaggtgc ggagagtggt gttaagatga 12360 aggggagagg caggcagagc cctgggcaga tgagcaacca gggcttagtg gatcacagtt 12420 aggactttgg gcttcagcca cagagcagcg gtgggctact gagatttttt aaagcaatag 12480 tgtgacaatc agatttgtcc tttttttttt tttaaagatg ctttgacaac cttgtgaaga 12540 aagaattgaa gggaagcaaa aggtgttgta gagagaccaa ttaaaaggtt gtcacagtag 12600 ttcatgccag agatgatggt ggcatggcct agcatgacgg tggtagaaat ggagggaagt 12660 ggtaagaggt aaaatcaaca agacttgccg atgggctgga tgtcggaatt gggggaagaa 12720 agctttctgg cctgagtaac tgggtgaatg aaggtacact tctctaagac agagaatgct 12780 ggaaaagaac cacgttcatg gatattgagt tcaatttgtg tgtactaaat ttggggtgac 12840 tatgagaccc ctaagtggag aagtagagtg tgaagctggc tgtatggata tggtactgca 12900 tgagaggttt tggctagaga aacacatgta ggatttgtca gcatatagaa ccctcagcag 12960 agccccagat agggatgagg ttgcctgggg agaggggagt ggggagggga ggggggaact 13020 gggggaggat tgtgctatgc ttagaggcca cctgagtgga catgggagat tccttctcac 13080 ggagctaagt gacagctgcg gctcagaaga atgcccttga tgtgaaaagg agatacccca 13140 agttcagagt agaaatgcag tgtatttttc tgggtcagct gtgtcatggg tcagcttaag 13200 aaccttcttg ccatgtgaca caatgattac ctgaggaaag catttaagtt ccaaaaggtc 13260 tattcccagg gaaagtggaa acaaaatttg tgagtgtgtt taggaccact ttagtctaca 13320 gaagggctaa tatagtgttt ttcaaacctt tctaaacatt ttggccacag aactttcatt 13380 aaagtaggat aatttaagtc tagtaaatga aatacaccct aantggctaa aagtatggct 13440 gttctgcctg cagcccctgc cttcaattcc caatgccctg cctcaagcct gtctgtgccc 13500 ccttggaagg cccagggccc tgtgggatgg acagcttctg agtgcattac ttctgagtaa 13560 accagttcta aaacctaagc taagtagatt acctgaaagc aatcaattca tgccctaact 13620 tgtctaggac atcaatgtaa ctttttatat agtataaagg tttcaccttc tttctggcct 13680 atgaatatgt ctgaaattca agagcaatta aagtactcct gggttgtcaa agccctttat 13740 gtaacactat tgagttatct ttatgcgtct gacttgtaag agatgcacaa ctctaggaag 13800 aagtagactg ctgtgtcctg tttccaggta tgtgtgtgtt tgccattttg ttgacagact 13860 ttaaaagcaa acatttctgg ccccaaccct gaactgccaa ggactggtgc tatgtaaagg 13920 gttctctgga tctgtctctt ccctaccatc ccagggagct cttaggaagg gaaagggcat 13980 agagattata ccagcctgcc ttgtggttag gaaccacccc ttggttggca tatagaacat 14040 gcttgttaaa aaaaccatgc aggggaaagt agagtctact accaggcgag agtttctcaa 14100 cctcgaccct attaacattt tgagccaaat aattttgttc tagggcattt tcctgggcat 14160 tttagaatat ttaacaacat atctggcctc tactcattag atgccagtga accccaagtg 14220 atggaaaaaa anaacaacaa cagaaaaaaa cctcttttat tgaggaaaaa caccaaactc 14280 ttccacatag ttgcaagacc ttgtgcaatt tgcctcctag ccaccactgt actcttgaat 14340 tgcacgcctg atgccaacca cactggttcc tcatgttcac catgccccct ccagccatgg 14400 gggtgtgtgg tcttctcaga gtctgaagca ttccccaccc accccaaccc accccctgtg 14460 gccttcttta accatgctgg ctaattcagg atccctagtt ccttatgact ttcctttaaa 14520 acgtctacca gaaattgggg gaaaaaaagt gttattatag gattaatgtt ggtcttccnc 14580 actatactgt gaatatcatt gagagcttgg tccctacacc ttaaatcccc catcgtcaac 14640 tattttttcc catctcagtg tcccatgatc aaggagaccc tccctgaatg tccagttccc 14700 caacccttac ccccagtcca gggtagcttc cttccttgtg cctctcatta acctgcatgc 14760 cgatccttca gtgcacttga ctcagtgtgt aattgtatat tcagtagcgt gttgttagat 14820 taaaatgtgg ttaatatgtg tttcaccagt tatactatga cactccttaa gggcagaaac 14880 agcatctttt ttaatttatt gatatccaag tgccctctat aatagatgct caataaacat 14940 tgaatgaaag tgggtgtcag ccagtactgg ccagactcaa actgaaccca ctgcttccca 15000 ctagcttgac tttttcctcc tgtttgtggc actctcttta aaacaaacca aaataaaccc 15060 aattttaaaa actttttaaa atgagcacgg atacagaaaa ccacacagaa caaatgtgta 15120 gcttaatgaa tttttttcag agaaataacc ttatgaccac caccaagtcg agcagtagaa 15180 ctttgctgtc cactaagaag ccctgtccat gtgccccatc ccaattacag catcctctct 15240 ctctccccat taagtaaccg ctagcctgac tcctgtaata atcacttcct tgtgagtttt 15300 tttagtttta ttatcgaaat atgcatcctt gacacaaatt tagtgttgcc cacttaatat 15360 atttgatgtc ttttagtcta cttaatctat ggattctcct tctatcgcct tctatgcctt 15420 actgattatc tatgaagaac ctgagctatt ccacctatag aatttcccag tctggatttg 15480 ttgattgcac actgatgatg canttcagca cattcctcta tgctctgcat ttcctcaaaa 15540 ttggcagttg gatccagaga cttgagattc aggttctgat tcaggttcag tccttttggc 15600 nagaccatag gaagcatgca attcctgact gtctctttat gatgttaaca gtaattagta 15660 tataatgcat agatctatta atccattggg ggctataaat ggtattattc taattttatt 15720 accttttcat ttaaaagtta gaatactttt gtacntgata ctacctctta tctattattg 15780 gttgctgttc acatagttta caaaggaaaa tcaggacaaa tgnttctttc tctttatttg 15840 ccagttttca tttataatga attgtttctc tgttattctc caaatttggc agattctttt 15900 ttaaaaaaaa tatcattatg aatgtatgga ttaaataatt gatgtatttc agtctcttgc 15960 aatcattatc ataattgtag cattgctttt taggcaaccc tggtacccag gctgtacatt 16020 tgtcatgggg agtggggagg gggagaaata gcatgggcac tntgagaccg agactgtccc 16080 tggcagccag tattctggca acactgttca cacccactta ctggatggat cttgagaaag 16140 ccccacttgg tggagcccat tcctgctgcc cttttccagc tggttatctg tcactctcct 16200 tttnttccca ggtttggccg gaagaatgtg ctgttcgtga ccatgggcat gcagacaggc 16260 ttcagcttcc tgcagatctt ctcgaagaat tttgagatgt ttgtcgtgct gtttgtcctt 16320 gtaggcatgg gccagatctc caactatgtg gcagcatttg tcctgggtat ggccatcagg 16380 ttggagttga gtacttgatc ctgtatttca ccatcatccc atcacctacc tttctggaga 16440 caactgtgat gtccctcaag ggggacaggg tttctaacaa aactagccag agcttcctgg 16500 tgaaccttac ttacaggcag ggaaactgag ccagacatga gaccagcctg ggtccccagc 16560 agcacaatgg cctgacttct gatttccagt tcttttctgg cctctgggct gtggctcctt 16620 ggtcttagta cttgntngtc aatttactag gactcaccag agatcctcca tttacaaaaa 16680 gggcctgcca ctgcacaggg ctgagccagc cccagaaaga gggnggcatg gttggaggag 16740 gaggggctgt gactggcaag cttgctaagg tagagaaccc cttgtctgca gagcactgtg 16800 gctggtgata tctacggaca agaataaatt gataggaagg ggctttcgtc accttcaggg 16860 ttttaattca gagtgcacac tgcagggctt tgtctcaaat gtgccagcct gttgtcactg 16920 agaagctgcc aggccggcct gtgtttggag gaacctgact ctagctgata aggcctttga 16980 gttccttggg ttgtattgtt gaaagggttg ttttttcttt ttatatttaa tattctttcc 17040 ttgaggctta agtcagcatg tgctgactta gtaatgactt cacttttaat aaattcttcc 17100 tcatgtgagg attaaagggg gcctaccatg gcatctttag cacatggctt cagaacatgg 17160 cgaaattttc aagagagaac tgttgcttgg gggcctgaga ggccacaggg atgtaccccc 17220 aggagacagt cagacaggag gggttcagaa cgccatccgc tccctagcgc catgaactta 17280 gagagagttc tcgctgtttt cttgtctgtg tattcacaaa gataccataa aaaattaata 17340 aggaaggaac ccaaattaaa ctgctaactc gacctccctt gttttgaaca gggacagaaa 17400 ttcttggcaa gtcagttcgt ataatattct ctacgttagg agtgtgcata ttttatgcat 17460 ttggctacat ggtgctgcca ctgtttgctt acttcatccg agactggcgg atgctgctgg 17520 tggcgctgac gatgccgggg gtgctntgcg tggcactctg gtggtgagtg tgaccctgtg 17580 ccccatgtgc ccactggcag gatgatttct gtctggcctt cactagaggg cagcaacaac 17640 ccatgaatcc ctattttgtc tcccagagac aggaagcata gattataaat tatttcagaa 17700 tgttttctcc acactcaaaa gagccaaaac aaaacagaat cccatgacag caacagactt 17760 gctctcagcc ctgtgctggg ttgccccaag tgtggggaaa aatagcagta gctgtgagaa 17820 gatggggtcc agcatgccct gtaggaagtt cccaagcctc agggcaggac agtgtaggcc 17880 ctagttctgg ctgtgtgctg ctgaagcctc atgccacagg cactggcacc aaaagcaaga 17940 gtcctcaggg tagccacatg gaggaagcca ggctccttct gcaccaccaa ggtagaggag 18000 ttgaacaggc agagaagagg ccattccaga ccaagagggg aacactgcag aggtgctaag 18060 gtgggaatca ccccttgcag gtggagaagg tgagatcacc agcccaagtg gagcagagag 18120 catttcaggg catagtggga gagtaagccg cacatcatgg ggcccagtca tgaccgaggg 18180 tggggggcgg ctacctggtc ccagcaaggt ggaaaataat atccatagag cnctcaagtg 18240 ccttgataaa catgctaatn tttttccttt ttttcttttc tttttctttt tttttctttt 18300 ttttttctca gacaaagtct ctgttgccca ggctgtagtg cagtggcgtg atttccactt 18360 actgcaacct ccgcctcccc agttcaagcg attctcatgt ctcagcctcc cgantagntg 18420 ggantacagg tgcctgccac cgcacttggc taattttttt tgtatttctt tggagagacg 18480 ggtttcactg cgttggccag gctggtctgg aactcctagc ctcaaatgat ccaccggcct 18540 tggcctccta aagtgctggg attataggag tgaaccactg cacctggcca aacatgctat 18600 tttaggtaga gtatctgact aatctgttgg ataaatcagg ggtagggtga ggagagaaga 18660 gaagctaaaa ggccagtgca gaagcttctg ttggtgccgg ggacagggag gagagtgtag 18720 cagggcctgg gctgacatag acatgcacag aagccaggct tccggagccc atcttgcacc 18780 catctcctca gcccagcaga tggcaacact gctcttcaga aatggaggtg gccagccagc 18840 atggggatgc cgtcaggggg tgcagggctc tcccattttt gtgcggtgtg gggtacacat 18900 aagctcatcc accccaggtt attgctgcgt gtggatcagc tctttgcttc tggcttgtga 18960 tcaccaaaca ttccacaagc tctggttctg caaccttatt cccacctatg gctgtgctct 19020 acctggtctg tgggtctgct gttggcaggg aggcctcact gagattggac cttgtactgc 19080 caggttcatc cctgagtccc cccgatggct catctctcag ggacgatttg aagaggcaga 19140 ggtgatcatc cgcaaggctg ccaaagccaa tgggattgtt gtgccttcca ctatctttga 19200 cccgagtgag gtaagcacca tgtgggtgtg ggtgagaggg acagactgac cgtgatttga 19260 gagcagcagc acccagccct gaagtcctcc ctgctcacag cagcccagcc ctctctctgc 19320 ccaagcccca actgcccatt ccccccatcc ccccactccc cacccccaca cgggccctgt 19380 taacactcag aagttgagga ataggttaca gctgcctcac tcttttcacc acgggtttca 19440 gattttcatt ttttacttcc tttctaggca atcatatatt ttaaccatta cttctaacaa 19500 taaatactct ttttgagtaa taggcctttc ataaagtcag catttgggaa aatcattgtt 19560 tcttatacct aaggtggctt gtcaccttac aaagctaacc ccaaacgtaa aatgtaaagc 19620 acaaatagat ttggagttag aagtatttca tctcttgagt attagcaatt attcattaaa 19680 aagaaaaaaa aagtgtttag tctctttctg ccctccaatg gttaattatt gcatatcatc 19740 ttggagtcag gtcctttttg atgtccacct cttcccccta ccccacccct cccgtcagcc 19800 ctgttctcac acaccatgac tcatttcttg gctctaccta gttcctggtt cttgcttttc 19860 cttcccgttc cctctcctac catctctgta gcaggcagtt ttccttggtc tcgtgactat 19920 gagaggttag aagctgtaaa tgctgcctgg tggggttctg gaatgtgtct gtggtctgac 19980 tggaagatga ggggttgggt gtgggaacag ccacaagcag ccctgctgaa gtgtgagagg 20040 caggcatggt tgggcttgga aaagagggaa cagttattgt agacagcgga ggccaatggc 20100 cactgccagc cctgcagact tcccagtgag tggtggccca gcagccactg tcagcatgca 20160 ccagaaaggg gtcctgtgcg caaaggtcag gcaggagtgt ggcagagggc ttttaagtta 20220 ggtggttttg ggggctttta agtgaggggt caatctgggt gaatgcataa gccccactgg 20280 catctttgag gaaatgaggc tatttcaggg gatactttca gtccaaagtt gaccttttgt 20340 tgaacttcta actctggaaa aacaagctcc aaacctgggt ttgcttaaga aagcaacatc 20400 agtgtgttta gacgtgtggt ttattaatgg ccttggctgt gctgaatttc ataggaagtc 20460 actctgggtg aagctcaggt caattttcct gtttttctat ttgaattctt tttccctgga 20520 agcacaccag taactacata gtataaggac tcaaaacatt aacttttaaa aaatatcaga 20580 ccaataaacc acacagccag gtactctctc tgacccagag ggcagggagc caggcttcgg 20640 gaggaatact tagaggcctc cttggaatgt ggccaccgac aggaatatgt gggggtgcag 20700 tgaggaagct gtcagcctgg gcctctgtct tcctgtaccc ttgagggact ggtcacttac 20760 ttttcctcat tttcattcac tctgatttnt tactgacaag gcctagggaa gttttcacag 20820 cctaaaacac agtcagtata cttactgttc ttagaaacgt aacactcccc gacgctgaga 20880 tgcagacagc taagatgcca gggattcaag tatgttattg tgtgctctga gtctctgacc 20940 acctcttctt cccatacact tatgatgttg ttcctgcagt tacaagacct aagttccaag 21000 aagcagcagt cccacaacat tctggatctg cttcgaacct ggaatatccg gatggtcacc 21060 atcatgtcca taatgctgtg gtatgtaaaa gagacctgcc tgaggcttcc agacaaagct 21120 tcttgaagtg gccattgggc ctcttgttta cagacatgcc tcagacaaaa ttcaaagcct 21180 atgtcatcag agagtgaaaa ggatatgtct tgtgttagat ggaaaaaatg ggcatgtcac 21240 aattcttaat gggatggaac ctcagaaaag gagaatgaaa acaattgtgg aggctgttgt 21300 gggaaatatg gactctngtg gggaatctct ccagatctta agatgaatcc ttgcccaatt 21360 tgggtcattt agttcccgtc tcctacccag ttaccgacag tggctgagga ggccaggtag 21420 ggcttttaag aaggatctga gtgaagacac catgtcctgt aggctgcaga ggctgccagt 21480 tactttctgg aaatgtggaa gtgggatgtg ctcctcctgg gatgtccata aacggtcctg 21540 gagtcagggc tatagcctag atgtccttac caggttccca ctaatgaggc aaagtatgtc 21600 agaaagggat ttgtgaatta ccagggagag gaaacatgtc caagtgcaca tcgctagctt 21660 ttgctcagcg gccgaaccct gggattctag gcgacntctg gagcctggtg ggttagcggt 21720 gagaagatgg gcgaggaggg cggacttcat ctcagagtcc ttattactag tctcatccag 21780 ctttgaggca gtcagccact gtgcctactg agggagtgct atgagtcacc cgcttccaag 21840 gaatggccca ggatccctcc aggcagttca ccattccctg agttggcctc aagacaggag 21900 cagcatgtag cctgcaccac agacatgcaa gcctgtgatg agtcacccac ttttgtgttc 21960 acccaggctc tcctccctgc tctggatttc ctggggactc atgcacatac tctttttatt 22020 gtaccagctg tgtgttccac ctgcagatga gtcaaaacag tctaatccat aaaggtctgg 22080 tttgtcaaag agtgtgggtc atcaacagag agaatgccta ctggggatgc ccaggtcagg 22140 ggtactgcag ggcatcctga tgagaggcag tgtggcccct ccattgggag ccacctctnt 22200 gctccacaag taccgcgggg ctggtgtcag ctgtctctga ccagcctctt cctgactggt 22260 caccacaggt agtgtgtgag ggtctctctc caagtgtttg acctaatgtt gttccttttg 22320 ttatcttatc ccccaaatcc tatcacacct cacttgatgt ctgcctcctg actcattctc 22380 tagctccttc tgcagttgct ggatttgagg aggttcagct taggattttt aaagctgaaa 22440 ggcaggttgg aatttttctt ttcaatgaag taaatctatc tgaattatac aagctttttt 22500 gctgggacac tgtctatatg gaaggctctg agagcgcact ggcgcagggt ttacactgta 22560 ccacttgggc tggggaaaat tatcttttga tctatgaagt aagacgcagg gttacagtta 22620 ctgctgcctt actagtctct gcttaaagat ggtttggaat ttactgaaat aattgcattg 22680 taaaagttgt acaggttggg aaagatgtgg atactgcttt tccagctttc ttctgcactc 22740 tgtttcagga tgaccatatc agtgggctat tttgggtttc gcttgatact cctaacttgc 22800 atggggacat ctttgtgaac tgcttccttt cagcgatggt tgaagtccca gcatatgtgt 22860 tggcctggct gctgctgcaa tatttgcccc ggcgctattc catggccact gccctcttcc 22920 tgggtggcag tgtccttctc ttcatgcagc tggtaccccc aggtagggac catgtgcatc 22980 tatggtttgg ggtcttcact gagtctctta ctgtctacca ggctgtctca attaataaag 23040 agaataaaat caagcccatc acagctccct tgcttatata cattcttggc ctaaaaatca 23100 atagaaagtg tcttctgaga ctagaacact tatggcctgg gctttgaggg agtgggaaaa 23160 agcagccatt ggggctgttg gttaatttta ctctgtaccc aagttaatgt gctcatactg 23220 ttttccactg cagaagaaga gggaagaaat agctatccca ttcctttttt tcctggccct 23280 gtcttcttta tttattcaac aaatagctat ggcatgccta ccatgggctg ggcactgtgc 23340 tcggtgataa cgatacacaa gaaaacaagc caggcagaac cccaggccct catggaacnt 23400 acaccctaga tgagaagaca gacaacaaac aagtaaataa aatgcttaat atagttcaga 23460 ctgtgttacc ttctaggaat acaaatgaag gacaatgccg agttagttta catagtcaca 23520 gatagtgtcc ctgaacaggg ggcagttcag tagaaatgta cataaagtga cagaaagccc 23580 tgaaaaagtc taggagaaca ttttaggaag aagaaatggc aaaggcagcg accctgagca 23640 ggggatgagc ctggcatgtt tgaggaggag ggagaagggg aggggccaga ccactgagag 23700 ggcctcacag anccttagca ggattttatt tctgaaacta tcttagtatc ccacagatgg 23760 gtgggaggta gccatttcca ataatttata gaacagttca tgggccctca tctctccctc 23820 tccatcactg tgcccagaga cttcagtgta cctgtagatt tgggagcctc tgatggtcac 23880 ttttgggccc atcaggctga gaacactgca cgggaacagc tccccatggg atgtggcagg 23940 aggagcccag aactgatgta gaggctcaca gctgagctca gagtgacctt caggtcacac 24000 atagctctcc catcagcaca gcacagagag attagaanat caactcgaga ttctgatggc 24060 ctatgatttt tttgaggtct gagtgggagg aaagcatgaa atgagttaga actgaattct 24120 ccattcatct aaacatcatg agttaattcc atagtgcctg cagtgtgagg ttctggggtg 24180 acagttaatc cctgacagac atgtctttaa tgacttatag actgggaagc aggttgattg 24240 gactattaag gagcttactc tggtggtctc caggttgagg aaagtgcatg tccttatagc 24300 tgcaggtccc agcctccttt cagcaatcaa tttggaggga aatcttggct atagcccctt 24360 cccccacaat aggaagtgat agaaactgac tccccaaaaa atttgggaag aaagtatgtt 24420 tgttttgctc tcaatagctg catgccatgg gttggtacct actcctaccc tctttccttt 24480 gcttctccag acttgtatta tttggctaca gtcctggtga tggtgggcaa gtttggagtc 24540 acggctgcct tttccatggt ctacntgtac acagccgagc tgtatcccac agtggtgaga 24600 aacatgggtg tgggagtcag ctccacagca tcccgcctgg gcagcatcct gtctccctac 24660 ttcgtttacc ttggtaagtc ccatgagcca agggcacact agagcaacgg gatggaagta 24720 ctaactggct tggagctgga ggttgcgtgt taacaggaaa acaagttcat acagtacatg 24780 ggctccatcc agtactggat ctttggccgg gaagggttct tgtcccagtg cactggccct 24840 cactttcaaa tggaaaacaa cctatagatt acctagaaat tgatgagaat attagagggt 24900 ttgtttctgt tttagccatc ccaggccttc catcagagac tacaattcct ttatcctaag 24960 aacctacaga gtggtttagg gagccagtgt gcttagttgg agaaatttct tggaatcaga 25020 gtttaaaagg aacatgaggg gaaagatgtc catgcaagag gtctgatgaa cgnaaaatta 25080 ttataaccta gagcactata gagtgatttt atcttgtgtg aagatccacc ccatgccatt 25140 ttatgtagca ggtctccagt tttctcttct cagaattatg tcttcatagc acctgtggtt 25200 tccctgcaca tccctagcca gtacctcttt agggagggtg gcacccacct gagagtactc 25260 agagtgcttt gtgaacatgc tatgtagatc tcaaagcaag caaaagcacc ctgcctaatc 25320 tgaaggcaga tcacatgggc tgggacacat ctgcagaggt ggaagagtta tttccatccc 25380 tggacaagta cctcaggttc cttggaaacc caaccttgnn aaatangaat aatcagcatg 25440 gcagaaatag gaataatcag catggcccag ctcttctcct gcaaccgccc ctttgtactc 25500 ctcccctgca tggtggaaca ctgctgggct ctgggcatgc ctgtgccagc tctgggttct 25560 gaaacctgtc tagatgccag attctaatct gactgctcag actgtgagag atgtgagacc 25620 aagaaggaaa gtgatcccct tccagagtcc tgggagcata aaggggtaga tgagagacca 25680 agtctaactg cagccctggg cctgaggctc cgtctgcttt gccataggtg cctacgaccg 25740 cttcctgccc tacattctca tgggaagtct gaccatcctg acagccatcc tcaccttgtt 25800 tctcccagag agcttcggta ccccactccc agacaccatt gaccagatgc taagagtcaa 25860 agggtaagaa gacctcctct gtcagtgttg atgcactggg tctgggtctg gccaggtctc 25920 aggagcccct cacaatagag ctactcgcaa actccctctc acagacacca tggactagtt 25980 tagccattaa agggttgtaa atggcaaggt gcttacttat agcccatcct ctctggtctg 26040 ttcctgtgtg gacatgtcac tatacacatc tccatggcag tagccgcact ggataactca 26100 gaggctagaa gaaacctttc agaatctgct gcaggattct cttcccaggg aagatatcct 26160 cagttcttgt ttgtttggag actgggaggc atctttttaa aatgtgttac tgacatattt 26220 ttgcttgttt ttatagaatg aaacacagaa aaactccaag tcacacaagg atgttaaaag 26280 atggtcaaga aaggcccaca atccttaaaa gcacagcctt ctaacatcgc ttccagtaag 26340 ggagaaactg aagaggaaag actgtcttgc cagaaatggc cagcttgtgc agactccgag 26400 tccttcagtg acaaaggcct ttgctgtttg ccctcttgac ctgtgtctga cttgctcctg 26460 gatgggcacc cacactcaga ggctacatat ggccctagag caccaccttc ctctagggac 26520 actggggcta cctacagaca acttcatcta agtcctaact attacaatga tggactcagc 26580 acctccaaag cagttaattt ttcactagaa ccagtgagat ctggaggaat gtgagaagca 26640 tatgctaaat gtacatttta attttagact acttgaaaag gcccctaata aggctagagg 26700 tctaagtccc ccaccccttt ccccactccc ctctagtggt gaactttaga ggaaaaggaa 26760 gtaattgcac aaggagtttg attcttacct tttctcagtt acagaggaca ttaactggat 26820 cattgcttcc ccagggcagg agagcgcaga 26850 <210> SEQ ID NO 42 <211> LENGTH: 54550 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (351)..(351) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (436)..(436) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (935)..(935) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1725)..(1725) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1874)..(1874) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2031)..(2031) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2152)..(2152) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2297)..(2297) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (2747)..(2747) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3477)..(3477) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (3535)..(3535) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4035)..(4035) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4084)..(4084) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4087)..(4087) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4321)..(4321) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4374)..(4374) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4394)..(4394) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4429)..(4429) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4480)..(4480) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4482)..(4482) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4704)..(4704) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4799)..(4799) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4800)..(4800) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4801)..(4801) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4802)..(4802) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4803)..(4803) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4805)..(4805) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4806)..(4806) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (4809)..(4809) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (5164)..(5164) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (5195)..(5195) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (5207)..(5207) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (6668)..(6668) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7458)..(7458) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7666)..(7666) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7687)..(7687) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (7730)..(7730) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (8656)..(8656) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9403)..(9403) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (9598)..(9598) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10245)..(10245) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10817)..(10817) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10829)..(10829) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (10895)..(10895) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11001)..(11001) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11049)..(11049) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11063)..(11063) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11067)..(11067) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11192)..(11192) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11294)..(11294) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11336)..(11336) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (11644)..(11644) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (12434)..(12434) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (12531)..(12531) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (12630)..(12630) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (12796)..(12796) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (13123)..(13123) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (13365)..(13365) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (13988)..(13988) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (13991)..(13991) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (14048)..(14048) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (14136)..(14136) 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LOCATION: (38835)..(38835) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38836)..(38836) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38838)..(38838) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38840)..(38840) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38842)..(38842) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38850)..(38850) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38852)..(38852) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38854)..(38854) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38856)..(38856) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38858)..(38858) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38862)..(38862) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38864)..(38864) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38873)..(38873) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38875)..(38875) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (38877)..(38877) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39427)..(39427) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39428)..(39428) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39435)..(39435) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39436)..(39436) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39439)..(39439) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39440)..(39440) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39441)..(39441) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39443)..(39443) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39445)..(39445) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39446)..(39446) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39447)..(39447) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39448)..(39448) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39626)..(39626) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39649)..(39649) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39671)..(39671) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (39961)..(39961) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (40088)..(40088) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (40602)..(40602) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (40653)..(40653) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41601)..(41601) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41796)..(41796) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41850)..(41850) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41863)..(41863) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41887)..(41887) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (41984)..(41984) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42114)..(42114) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42436)..(42436) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42630)..(42630) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42631)..(42631) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42632)..(42632) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42652)..(42652) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42715)..(42715) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42850)..(42850) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42902)..(42902) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (42946)..(42946) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43373)..(43373) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43408)..(43408) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43409)..(43409) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43512)..(43512) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43657)..(43657) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43765)..(43765) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43777)..(43777) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43825)..(43825) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43905)..(43905) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (43934)..(43934) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (44380)..(44380) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (44422)..(44422) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (44559)..(44559) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (44790)..(44790) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45124)..(45124) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45125)..(45125) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45155)..(45155) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45157)..(45157) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45158)..(45158) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45172)..(45172) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45468)..(45468) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45714)..(45714) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (45987)..(45987) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46036)..(46036) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46042)..(46042) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46056)..(46056) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46090)..(46090) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46094)..(46094) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46110)..(46110) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46112)..(46112) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46114)..(46114) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46121)..(46121) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46134)..(46134) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46144)..(46144) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46146)..(46146) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46149)..(46149) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46176)..(46176) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46177)..(46177) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46200)..(46200) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46223)..(46223) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46447)..(46447) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46713)..(46713) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46886)..(46886) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46906)..(46906) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (46987)..(46987) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (47006)..(47006) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (47406)..(47406) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (47442)..(47442) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (47729)..(47729) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (47851)..(47851) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (48512)..(48512) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (48051)..(48051) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (48512)..(48512) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50116)..(50116) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50789)..(50789) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50790)..(50790) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50791)..(50791) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50793)..(50793) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50794)..(50794) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50795)..(50795) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50796)..(50796) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50797)..(50797) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50799)..(50799) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50801)..(50801) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50802)..(50802) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50803)..(50803) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50805)..(50805) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50806)..(50806) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50807)..(50807) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50808)..(50808) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50809)..(50809) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50811)..(50811) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50812)..(50812) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50813)..(50813) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50814)..(50814) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50816)..(50816) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50817)..(50817) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50819)..(50819) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50820)..(50820) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50822)..(50822) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50824)..(50824) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (50937)..(50937) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (51301)..(51301) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (51327)..(51327) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (51896)..(51896) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (52444)..(52444) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (52666)..(52666) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (53747)..(53747) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (54085)..(54085) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (54153)..(54153) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (54251)..(54251) <223> OTHER INFORMATION: n can be a or t or g or c <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (54520)..(54520) <223> OTHER INFORMATION: n can be a or t or g or c <400> SEQUENCE: 42 catgagcaga aggcagatga cagctgccat aatggaaaat agtatttcct cataaatttc 60 cttgatctag gccagttctc aggctcagag cctattgatt taaggaaagg ccaagccttt 120 ttatagaaga gccctccaat gctgccaaag gtatacaaga taattatttc cccaatcttt 180 ccacatgaga gatctgtggc catttatcat agtaactctg gtcaggggga agaaaaagaa 240 ccagactttc aaaggctatt gggtacagag tatgagctgg catcagtgct ggggggaaac 300 actatcatgg tccccccgtg acagaggctc atgaaagcca ggtaaatgga ntactcttgc 360 aaacagatcc agaagtctga agatccacac tgtactaatt tccttatccc taagtaaata 420 actaggacag atgttntagc aactggcagt acactaacat ttactcccta ttttattaag 480 agccattaag gtaggaaggg ccaaatgaaa gcccctgaca cttaccctca cctttcttac 540 tgatttatta aatgagaagt aaaaccacat cctgggtggt attgcagaga ttaatttcaa 600 catcaaatat tttcttctca atatccttca gtcaggagga tgaaaaactg tttgctttta 660 tgtaggaata atagcagtac atattcactc tcttgcctct gggctatgtt agttctcctc 720 tctgcacaac acagtatcta gcgactttga ttgtctcaat attccattga acatcatggt 780 agtccactgt attgatgacc taatgctaat ttgacctagt aagcaagaag aagcaagaac 840 tctagatgtc ctagtaaaga cacatgtatg ccaaaggata gcagataaaa atatgaagat 900 tcaggacatt catattgttc aacttttttc ttacnttttt gttctagaat aagttaaatg 960 gatgtaaaag tagacaaact agtaaaacga atcccttgaa ccactattca cagcccatat 1020 tatttcatct atatccccac caacttcttc tatcccatat tattttgaaa caaatgggta 1080 aagttatcag ggatcagtag tcatgccagg ttatcccctg taaagtaaag acaagttatt 1140 gagctctgta tcctccaaca ctaaggcata gtgcttggtg gagtattcct ctgacccatc 1200 tatttcgtgc ccctgaaggc tttcagtttc gggtgaaacc cagagcagga gagagctgta 1260 cagtgtgtcc aactagagta caagcttctc taccatttgg ttcatattat ccagcagata 1320 caatggggct agaggcatac atgatgaata aggctacagg gcagagtctc tgacatgccc 1380 taataaaaga gtttcagcac agatctctaa agttctggag caaggccatg cagcagagag 1440 atattcgact tttgaaaagc agctgtttgg ccccaataaa aaccaagagc ctagcaatgg 1500 gacatcaagg gtctatgcaa ccagagatac ccattgtaag ccaggtattg tcagagtcta 1560 ccaagtcgta agattaggca ggtttaagcc aggcatggtg gctcacacct gtaatcccgg 1620 cactttggga ggaagctgag ggcagagaat tacttgagcc caggaggcaa catggcaaaa 1680 ccccatctct aaaaaataaa gaaaaaaaaa ttagctgggt gtggnggtgt ttgcctgtag 1740 tcccagcaac ctgggaggct gaagtagaag gattgcttga gcctagggag gttgaggctg 1800 cagtgagctg tgattgtgcc actgcactcc agcctgggtg acagactgag aatctctctc 1860 aaaaaaaaaa aaangcagac ttatcagcaa tccatcatat aataatagaa caggaatggt 1920 aaattcagga tcaggactaa gcaggtcaat agggtgcatg taagtcaaca aaaggtggct 1980 cagactccta tgacacctac ctcagctatc ggctatacca acccttctgt nttagctcag 2040 acctacagcc ttagtaggta gttctctgta accaactgat ggaggggaaa atagccctta 2100 ctcacagatg gattagcttt agacattgat actagttaaa aaagaaaaaa anaaaaagag 2160 attgttcctg taacatagct ccatttaggg ggtagcccta aacaactttg aagggaaatt 2220 cccccagtgg gctaagctgt aagcagtata cttgttcatt cattttgtat ggaggacaaa 2280 acaattccag atagagnttt acatacactt gtgagcaatg gcaaatagtc gagtggtacc 2340 tgttcagccc tcacttatgt gcaatctgga agtgcaagca gttgaccaat ggagacagaa 2400 ctaggaaaca aatacctcct cattctatat ggctctttag aagcccccag tgggattaaa 2460 cctcagtaac ccacagcaat ggggattgag acaaggctga ggtgaggaaa aagagcaagg 2520 cacttgtctc tggtgcaaat ttaaggaggc accaagaaat tcagtaacca agattaatta 2580 tattttaatg caatattttt taaaatagaa attaatgcaa atacccatga tgaacgcaat 2640 atcaaaattt tcaataaaga caggctcagt attgctaatt ttccatttat tcttaggctc 2700 cactagggct ccacacaaca ctgttactga tcttggtcat cgccaanaac catctcaatt 2760 tcacagtcta tgttggcttt acctccctct ctgttcactc tcctccctag tccctcactt 2820 ctgttttatg gtatcattac tcagaataaa cgaccttata tacgttcttg tctccaactt 2880 tgctctatta tatggggtgg agtagggaga tgaaacccaa gctaagtaag ataatgacca 2940 taatatatca ttcgaagaag gatacttgtg aaagtaaagg gaggctctat taataatttc 3000 actggattaa taggcataaa tcagagctgt cctagcacat caggatgtat agtcttatta 3060 caggtaggaa actgaggttc caagggggtg ggaagtcctc ctaagaggag gggtcagact 3120 ggaagctaca caaaaagagg cagaaatgtc cctccgcctc ttaatcggag cctggggaaa 3180 caaacacact cgtgcaaaat ctccaaagag gtgagctctt caccctgtca attttatctg 3240 cctcgtgaac cccagggctc aggctccagg cccgggctag ctcacacaac agcagaaggg 3300 ccttaggtct gggcactgag ccaaaaaaag ggaggctgtg gtccctgctt tggttaccct 3360 gccgggtctg agcgccaaat cggatctcct acttctctct ccctccctcc ctctgttcct 3420 ggactggggg caggcccttc tgctaacaga aagccttcca gtcggagaaa gctctgncag 3480 cctgccgcga taaagggccc tgggggcgtg aggagagcaa ggggctcaaa atcanaaccc 3540 agcgtgacga cagtgcctcc atgactgtgc tcccgcaatg cgcaggctcc atgtcctggc 3600 gcccgcccgc ccatggaccc ggcgggggct tccaggctgg gctcagccat tacgccggcg 3660 tgcgggggag gaaactcgcc tcccgggcac tcggttgtct cctgcccccg cccctccctc 3720 cgatccgggc ccatctctga cgtagtgtga ccttgctcat cccttccagg ctgtgggcct 3780 gttttccctg tgcaagatga gggtcctggc tgtcctgagg acgctgtccg ggcgccgcca 3840 ggggtgaccg aattcagctc tgctaggact gttgggaaat gagctccctg tcggcgtgtg 3900 ccagccgcct gcgcgaggcg ccacaggaga gggcgcgctc ctgtcgctct gccgccccca 3960 gaagtttccc gggaaccgac tccactgact cgcccctccg cgccccacgc gtggcagcct 4020 aagctcagcc tccanattgg aggagaccgc ggagggaacc ctgctggggt ctgggcccgg 4080 ggcnacncgg cccgagcaga tcgagggccg acccctccga gaactcgctc tctggcctcg 4140 gctcctccct tgcgcccgcc ctcccacgtg gggcccaggt ctgggaatca gcgctcgggg 4200 gtggctgggg acaaccgaga acgagcttct tccccggcac gcgggcggaa tggctgagcc 4260 cagcctggaa gcccccgtca ggtccttggg ggcgggcggg cgcgcgaagc acagggcgga 4320 nacagccggg agcccagcct cccgggctgg gccgccctcc ccttccccgc gccnggccgg 4380 ggatgggggt gtgntcccaa gtgtacagtg gcatcaagct cagcgcganc tcccgggaac 4440 gctccaacgc cttcagcctg tttcccagga acggtccccn gnttcgcgcc ccaatttcta 4500 acagcctgcc tgtcccccgg gaacgttcta acatccttgg ggagcgcccc agctacaaga 4560 cactgtcctg agaacgctgt catcacccgt agttgcaagt ttcggagcgg cagtgggaag 4620 catgcgggac tacgacgagg tgatcgcctt cctgggcgag tgggggccct tccagcgcct 4680 catcttcttc ctgctcagcg ccancatcat ccccaatggc ttcaatggta tgtcagtcgt 4740 gttcctggcg gggaccccgg agcaccgctg tcgagtgccg gacgccgcga acctgagcnn 4800 nnncnngcng aacaacagtg tcccgctgcg gctgcgggac ggccgcgagg tgccccacag 4860 ctgcagccgc taccggctcg ccaccatcgc caacttctcg gcgctcgggc tggagccggg 4920 gcgcgacgtg gacctggggc agctggagca ggagagctgc ctggatggct gggagttcag 4980 ccaggacgtc tacctgtcca ccgtcgtgac cgaggtgggt gccaggccga gaccgttgac 5040 ccgggagtgc ctgaccctcc ctctgcgtca gccccccttg agactccctg cgcagtgccc 5100 gggtcagcgc tcccctcccc ctcaaacctg ctgttcatac ttccagcagc gggtgtgcac 5160 cccnagaaag aataggactc acgcgaggcg cattnctggg tcgtttntgt ccaataagga 5220 ggtgatggag aaaggagttt gtcaccaact gtcttttcat ttccgatttt cacaacaaat 5280 gaagtttcct aagaacctag atgttgcgtt gggggaagcg cagcccaggc tacccagacg 5340 cactgcctga gtcaccttcc tgccaggcat gggaggaggg gtgtgaggga ccttgttact 5400 gggcagggcg gggccaaatc ttgtctgttc cctggccaca gacttctgga ggcatcagga 5460 ggtgtactgc cgtaccatat acttgtgagg tttggggtcc tttcctgagg ccccagtttc 5520 tctaagacag cagatggcct cctgaggctc attgggtgca aggaagcaca gaaggcgaaa 5580 ccccagctgg aagccctggc cctcagggac ctctctgagc acagggtgag ttggcaggca 5640 ggggctgtag cccctcagca ccctgcgtgg ttagtggcag gttttctaag ttccaggaat 5700 gaggatgcac acacacttct cccgcttttg ctgcttcaca tctggtaagg acctgggtca 5760 ggatacacct ttcttctgag gagagcatcc tcatggagct gttgcctgct attggtcagg 5820 caggtaggat ttccctgctg ctagtccctc ctctgcctca tgctcctccc aagaaaaacc 5880 tgagtggcct ctgctagtcc cttatccctt tccctcagca cggtatagcg gtcatcagac 5940 attgtgtctg gccttgtgct gagcactaag gtgtggacat ctggtgtgtg gagcctaccc 6000 tcagatgccc atggggcaca ctggctgtgt tactgagaag gctaacatta accctggtta 6060 gcaatagggt tctggaaccc aaattcaagt cctgccttgc ttgctatgtg acctgggata 6120 aataaatcac cctctctgtg ggacaatagg tggaggaaat actccaagaa ggggtgatat 6180 gattttagct gattctgaaa atgtgagcaa gacctgtcta ggcaagagta tgggaaattc 6240 aggtaatgga attctcatat atcggagtgg ctggaactca agggatgaca gatatgacaa 6300 atgagactag aaatggccac aagggctagt tcatagtggc cttctatgta tactgaggag 6360 ctgactttat tcggaggaca gtgagaaaat agtaagcatt ctaaggccag gttcgtgctt 6420 ttggaaagag ctcactctag ctgctatgat aaacaagaag accagtgagg aagttttgaa 6480 actctcctct gcaagagaat ggtggccagc caggcgtggt ggttgtcgaa tctgtggcac 6540 ctgtgggaag tgggctcagc ccagggactg cctttggatc ccccagcatt ggcaccatac 6600 ctaccctggg ccctaaggtg gccatgcttc tctggatttg cttccctagc aggggctcta 6660 gtgcttgncc actccctgcc cacagcatgg cctgggagca gctgagactg ggggccagct 6720 catcccgcgt cgattcctgg aagtgttatc agtgcctgtt atggaggctg gacccatgag 6780 tggcagcctt ccctggcagc tgggctgacc tgtctgcttt tccattgctc gctggttttg 6840 ttcactgtag ggcgtgaggg gtgagtagct gctggcctcc aagtccatag ctactcatgt 6900 tgtacgctgt tcacagggac ctctaaggat gtacatcatc acacattcac acacatgcac 6960 caggatttgc tttttttggc agcttttccc ttcctggctt cctttttgag tggtggaagt 7020 aaaataaaaa gcaactaggg gctgggcaca gtggctcacg cctgtaatcc cagtactttg 7080 agaggctgag gcgggcagat tacttgaggt caggagtttg agaccagcct ggccaacatg 7140 gtgaaacccc gtctctacta aaaatacaaa aattagctgg gagtggtggt gcacccctgt 7200 agtcccagct actcgggagg ctaaggcagg agaatcactt caacctggga ggcggaggtt 7260 gcagtgagct gagatcacac cacagcactc cagcctgggt gacagagcca gactgtgtct 7320 caaaacaaac aaacaaacaa caacaacaac aaaaaactgg gctctggtgg ttgggaggag 7380 gagggaagga agcaagtacc agggtaagca ggatggatgg atggctctcc cccagagggg 7440 cggcagcaca cagagttntg gagtcagact cagtagaggg ccagttttga ctccactgcc 7500 aaccacctgg ctgactccag gcaggttaca tcactgatga aagcctcagt ttccttgtct 7560 ataaattggg ggtacaagcg atgaaaagag gctcaacatc actaatcact agggaaatgc 7620 aaatgaaaat cataaggagg taccactttg tacccttaaa aatagntact acaaaaagaa 7680 aaaaaanaca cccagaaatc cactttggga ggccgaggca ggaggattgn tagggggcag 7740 gagttcaaga cagcactggg caacatagta agaccccatc tctacaaaaa ataaataaaa 7800 aattagccag gcatgagggc atgtgactgt agttccagct tctcaggagg ctggggcagg 7860 aggatcactt gagcccaaga gtttgaggtt gcagtgagct atgaccatat ctctgcactc 7920 cagcctgggt gacagggcaa gaccccacct ctaaaaaagt gttgttgttg tttttaaaca 7980 cagaaaataa caagtgttag tgaggatgta gagaaattga aacccttgtt cattcctagt 8040 gggagtgtaa aatggtgcag ccactatgga aaataatgtg gtggtcccta aaaaaattaa 8100 aaatagaatc accatatgat ccagcaatac taattctgga tatatgtcta aaataattga 8160 aacagggttt caaagagata tttgtacacc atgtctatgg tagcattatt cacaatagtc 8220 aaaaggtgaa agcaacccaa gtgtccttcc acagacaaat ggataaacat aatgtggtat 8280 atgcgtacaa tggacgatta ttcagcttta aaaaggaagg acatgctaca acgtggataa 8340 accttgagga gactacgctt agtgaaataa gccagtcaca agacaaatta ttttctgatt 8400 tcactacagg agtagtcaca ctcacagaag cagaaagtaa atggtggttg ccagggactg 8460 gaagaaggaa ggagtaggga gtcgttgttt catgggtata gagtttcagt tttgtaagat 8520 gaaagtagtg ttggagattg attgcacaac agtgtgaacg cttctgaact gtacacttaa 8580 aaatggctaa gatggtaaac tgtatattat gtgtacttta tctcagtttt caaaatgggg 8640 ataataagag aagccncctt atctgagttg ttgggaggac tcagtgagat aatgccccat 8700 gccccatccg gtggtggcca gcacagagtg tggcaccagc aaagagtgtg gcaccagcaa 8760 atgggcttcc taggtggtgg tgaggagtgg taaaggcaga agctcagcac cttctttgcc 8820 ttctccactg gctggggaca gtgggcatgg tgggagctgt tctaaagtcc aggttgtggc 8880 ctgtgtaata ggtgatggga cttgctggag gctgagcccc tctccccaca gtggcagttc 8940 caagcctcag agaatagaac acaagtccaa acccatactg acttggccag tgccagtgta 9000 cagggccaag cccagggccc ctgagaaggt tctctgcatc ccagttggca caacacaggt 9060 agtgggactg tcctcagatt gtgtctttgc cttatactgc cgtgccagga tctcccaatg 9120 ggcatatctt tggggacaga caagtctgcc tgaactgccc cccaacacct cttcacagga 9180 ggacagggtt agccaggaac caaggatggc atgctgtgct gtagaaatgc ctttcatagt 9240 atgccaggag gtagcaataa ggtgtctgag ttggggtttg cgtgagtgca ttcgtctgtg 9300 tgtgtacatg tgtataaggt agtttccttc ttcaggggtt gattgtgagg tccaagtttt 9360 tcaacctgtg cagttactaa gagtcaaatt atttttcgtt ttnttttatt ttattttatt 9420 ttattttatt tttttgagat ggagtttctt tcttcgttct tgttgcccag ggtggaggag 9480 tgcaatggtg ccatctcggc tcactgcaac ctctgcctcc ttggttcaag cgattctcct 9540 gcctcagcct cccgagtagc tgggattaca ggggcctgct accatgcccg gctagttntt 9600 tgtttgtttg tttgtttgtt ttttgtattt ttagtagaga cagggtttca ccatgttggc 9660 caggctggtc tcgaactcct gacctaaggt gatccacctg cctcggcctc ccaaagtgtt 9720 gggattacag gcgtgagcca ccgcgcctgg cgattatttt ttaactttat tttgaaataa 9780 cttttgattt agagagaagt ttgaaaatag tacagagatt tcacatatac ccttcatcta 9840 gctttctctg atgttaacaa tttaaatacg cgttatgcat ttatccaaac caggaaatta 9900 acattggtta caatagtaat aactgaacta cagactttgt ttggatttca ccagtttttc 9960 tactactgcc ctttttctat cgtaggatcc catccaaaat cccatgttgt atttagttgt 10020 catgtctcag tctccaatct gtgattgttc cttagtcttt ccttatcttt catgatcttg 10080 acatttttat gagtattttg atgaatgctc ctcagtttgg gttggcatga tttttctcac 10140 aattagattg cgttatgcac tttttggtaa tgatacctta gaagtgatgc attctctggg 10200 catcatacca gtgggtacat gatgctgatg tgtcttatta ctggngatgt taaccttgat 10260 catttgtcaa gttggtgtct gtggaatttc tctgctgtaa aggtactatt ttttcctctg 10320 tcactaataa atatcttaag ggaggttctt cgagattata caaaatcctg tgtctcctca 10380 aatttttatt cactgatttt agcattcatc actaggtctt gactgaaaca attattactg 10440 cagtttgcct agtgatgatt ttgcattttc tgattccttc aacatttatt aattggaatt 10500 cttctgagaa gaagagcttc ccctccacat ctatttatta atgtatgcaa ttgttaactt 10560 atatcagtac aggttcatac atacttattt tatttcatca gttataaact aatgctatcc 10620 atctttattt tgttgctcca gttattctag ctcaaaccaa gttatttttc actttaagga 10680 tagagaatgt agatatccag ggtaagggcc tttatctgtc tctgcagtca gggctagagg 10740 agtctgtgtt tacccctgcg ggaggagtgc cagtcacagc tcgttgctaa gttttccatc 10800 aggcagcagt tgagcangaa cgcaagcang gactggtggg acctgggttg ggactgaagc 10860 ttctgttggg gaaggaagtg ccccaagcaa cccanagtgt ctgatgctgg ggtcctcatc 10920 cctgagacct actgcagggg tcagatctca gtctccatgg gcatggccct tcatatatag 10980 ccctcagggc caagacctca nagagaagag gccctgcgtg tgaggaaacc cggcagcctc 11040 ctgccctgng gctaaaggag cangaanggc aacaaatgct ctgctctgga gagggcctaa 11100 gttcatctgc agggccacag ggcaagcagc agaggcaatc ctggctcgtg gccaggggct 11160 aagcatgggc tggcctttgc ctcaagcatg tnctcttctc ccatggagca tcattagggt 11220 cttgaccttc ccatcagtcc atgggctggg aaaactgagg cagtcacctc taagctggat 11280 accacttctg ccangtcttg tgctccagag gccctggggg aaccttgtgt gttaangacc 11340 agccttcttt gcaggccacc agtgatctaa gacagggctg ctgccacacc gtagatcctc 11400 ctgtcctctt ctgcagctgg gctgcctcct ctaggaaccc tagtggagct gctggtagcc 11460 cactggtagt ggagttgatg gagcctccag caaagggcct ggacctctgg tggcactagc 11520 cttgtgcttt cctgggaact ggggtcaggg cctgaacagc agtaggactt actgattccc 11580 cacccataac ccagaggcga gccaggttat gtggcgaagg ataaggcctc ttcccctgct 11640 aacngggaac ttctgggagg cactgagagc agcaagcaag ggaataatga aacagactaa 11700 ccctcacatg cggctgccac tatgtgggac ttcacatagc ggctctcaag gatgcacctc 11760 ccctggggtc tgggtaggcc ccgacaaaag gggaaaacct tccgtgatag gcaggtttgt 11820 ggagtttcta tcaggcctgc aggctgccct gggacattgc tcacgggtgt ggagactgtc 11880 aagatagcct gaatattaac caagttgatc atccaagtcc atactcagac ctgccctctg 11940 gcagattcca aaggggataa ggtgtggggg cctctggctc cagccagccc ggcgagactt 12000 ctatttccag tcaatgcttc agaaagtaga tcttgccaga gagcacatag aggagactca 12060 ggggcttccc cttgctctgg cctgaatgtg cttccctgtt tgtttatcag ctgcctcacc 12120 ccaaactgtt tgcctctctg ctgtgttcct ctgacaacag ccaccaggat ctcagaatat 12180 gcttttgttc agaggctgct tcacctgcac ctcctgccaa gtttctggat aaacagactt 12240 tgtccatccc tcttggtggg cagcagaact ctcagacaga gtccaaggtg gcattttgac 12300 aaaaacaagg ctttgacagg actggtcagg gggagctgca ggtaccttgg gcctctagaa 12360 ggactgtaat tcctccctta tggcaggctg cattcaattt aggtgtaaga ctaatacagg 12420 tgtgccttgt tttntaaagc tgtgttgtgg ttttatgcat gtctctggag tccaaaagaa 12480 aggcaaggat ccccatttgg aatgaagaag gtgtggagag aatggacgtt ntggggaaag 12540 gctggaatga cccacatgct ctagcaagaa gcacagacag tccaaggctg gtggctcctg 12600 ctcagcattt gcaagactgg agggcaggtn caggcggcaa cttccagagc ttcccctcag 12660 tgcttggtga ctggcacaga cacgatgcca tttgctcatg ttcccctaat acagactggt 12720 agagctgtgg tggatccatt gtcaggatgc aaggggcaca gccaggtccc tgagtgaccc 12780 ttctccttcc cacagnccct ccactcccat ccctatcttc ccactcacac tcactggttc 12840 ttctgctttg gtttagcctc caatgatcac agaactcatc agtgaggctt ttccatctgt 12900 ggtagctttt ctaatataaa gaaagaaaga tactgagaac attttaaggc ttagcagcct 12960 tctggcttag ttgtttgtaa atgaaaatat gagtagaaga attaaacagc caaaaagata 13020 acccacaaaa tgggagaaaa tattgacaaa tcatatatct gataaaggat ttgtatctag 13080 aatataaaaa taactctgat aactcagcaa taaaaagaca acntgattta aaaatggata 13140 aaatcatttg cccattttgg agaatagatg ttttgccaaa gaaatacaaa tcaattagca 13200 catgaaaaga ttctgagact tcgaagttag cagtgtgagg agcgccagcg ccatagacca 13260 gctcctcagt gaaacagcca taactggtga aaatacacac acacacacac acatttagag 13320 tctctggaag ttgtcctaag ggcatatatt tattcaagaa agtcnactat accttggcaa 13380 gaacagtgaa gtctatgata tttgagtcat aactccttca gccctcccct tccccttcct 13440 cccagcacaa gaaaaatgga agttccactc taggtgggta tggccaagaa aatactgttc 13500 tctctcccat cagcttccaa ggaagggcta cagcagccca ccaagaggga caaccaatgc 13560 ccatccccca cccatccctg tattctctta gctccaaacc acagaaggta aaatcctcgt 13620 gagtgcaacc aggggatcat aggttcccat cctccaccca ccgcctattc atatagtaga 13680 gactctactc caggtgccac aagttgagaa tattagagcc ttgattgccc ttatcccagc 13740 tcattcatac ggcagagatt ccacaccaag ctcccacttc cactcagtgt ctgactcata 13800 aagtaggggt gtcattctga gataaatggg ccgctttccc tgcctacctc tctacaacag 13860 gagctcagat attttgccca gcggggagag ataatccaaa agaacagagt tctaaagctg 13920 tccccacagg aacgaacttt atttgaaata gagtgtgtga aaggacagcc taagattgct 13980 ctcaaganca ntggagaatt tagtggtaag caactaaaag gattctggta actccattag 14040 agcaacanat gaacccataa tgcagctagt ttaccaggaa aaaacagaaa acaaacaaac 14100 aaacaaaaca agaaagagac agctaagagc agcccntctg gagtcaaaac aaaccttata 14160 gatttgcctc aaaaactacc actgcaaaga ggcttgacgt caactggatt agactgtggg 14220 acaatatatg cccccagggc attattgaaa tgaatgaggc aactggctag caattagtga 14280 ggctaacagc tgggtgtgat accagcagac acagacagct taatagaaag atcagactgg 14340 cgtggnggct catgcctgta atcctagcac tttgggaggc caaggcgggt ggatcacctg 14400 aggccgggag tttgagacca gcctggctaa tgtggggaaa ccccatctct actaaaaata 14460 caaaaattag ctgggcatgg tggcaggtcc ctgtaatccc agctactcag gaggccgagg 14520 caggagaatt gctggaaccc aggaggtgga ggttgcagtg agccgagatc atgccactgt 14580 actctagctt gggcaacaga gtgagacttc atctcggaaa agaagaagaa gaaagatcag 14640 ggaaatgggg gtggaagaat gtgacagtac ctaatttcta caatatatta tctaaaatgt 14700 ccagttttta accagaaatt acgagatatg cagagaaaca gaaaaatatg acctatacat 14760 ggggggaaaa cgtgggcaac agtaactgcc tgagagggtc cacatgtcag attttaacag 14820 actttaaggc ataaggcagc cnttataaat atgttcaaag aatgaaagga agtcatgctt 14880 ttaaaagtnt gatgacaata ntgcatcaaa tagagaatag caataaagag agaaaaatta 14940 catttatatt tttaaaagct gagccagaca tgatggcatg tgcctatagt cccagttact 15000 caggaggctg aggtaggagg attgcttaag cccaggagtt caaccccagc ctgggcaaca 15060 gaaagagacc ttgtctctta aacaaacaaa acaactgaat agaacttctg gagtaaaant 15120 atacaataat tgaaatttaa aagtaactca agggccttaa cagaagattt gaacaggcaa 15180 aagaaagaat cagcaaactt gaagatagag gattggaaat tatgcaatcc aaagaacaga 15240 gaggaaaaag ggaataaaga aaatgtatag agtctcagag aaatggggaa caccattaaa 15300 catagcaata tatgcataat agaattacta ggagaggaga gagagagaaa agggcagaaa 15360 aaatgctcaa agaaataatg actgaaaact tcccaaattt ggtggaaaac attaatctac 15420 acctttcaga agctcaacaa actccaaata gaatgatcac aaagagatcc acaccctgat 15480 atatcatggt aaaactgctt aaataaaaaa agagacaaaa acgaagggaa aattttgaaa 15540 gcagcaaata tatgactagg tacatacaag agaactccaa taagatcaac gtttgacttc 15600 tcattagaaa ccataaagga cagaaggcag tggagtggca tattctaagt gctgaaggaa 15660 aaaagaaact gtcaaccaag aatcatgcat ccaacaaaac tgtctttcaa aactgagata 15720 aagaaattca aaaatacaca aaacttgaga gaattgtttc tagcagtgat gtcttacaag 15780 aaatattaaa ggaggcactt cagaaataaa tttanccaaa aatttgcaaa atgtatactt 15840 taaaaactat aaaatgtcat tgaaagaaat tccagaagnc cttaacaagt ggaaaagctt 15900 cccatgttct gttcatggag cagaagactt attgttagta tggcagtgct ctccaaattg 15960 atcaatagat tcaatgcaaa agatgttcaa cattagttat tagagaaatg caatcaaaac 16020 cacaatgaga tacctcttta cacccactac aatgactaaa attaaagaca cacaataaca 16080 agtactggta ggaatgtgga gaaattgaaa ccctcattca ttgctgttgg gattgtaaaa 16140 tggtgtagcc actttggaaa gcagattagg agttctgcaa aaggttgagt atatacttac 16200 cgtatgaccc aacaatttca ctactatgta tataccccaa agaaatgaaa acatgtacac 16260 acaaaatgtt gtacatgaat gttcacagca gcattattca tagtagccaa aaagtggaaa 16320 caacccaact acttatcaac tgatgaacag atcattgaaa acgtggtaga cccaaaccgt 16380 gaaatatata tatatatata tatatatata tatatatagt tgttgttgtt gttgttgttg 16440 agatggagtc tcactttgtt gcccaggctg gagtgcagtg gtgtgatctc agctcactgc 16500 aacctccacc tccaggctca agcaactctc ctgcctcagt ctcccaagta gctgggatta 16560 caggcacgtg ccaccgtgcc cagctaattt ttgcattttt agtagagaca gggtttcacc 16620 atgttaccca ggctggtctt gaactcctga cctcaggtga cccacccgcc tcggcctccc 16680 aaagtgctgg gattacaggt gtgacccacc gcacccagcc caaaccatgg catattatta 16740 aaccataaaa agtaatgaag tgctganaca ctgcacaatg acatggatgg acttagaaaa 16800 ggagctaagt ataagaagcc agtcataana cnctatatat tgtatgattc catttatatg 16860 aaatgtccag aataggcaaa ttcatagaga cagaaagtag attagtggtt tccaggggct 16920 agaggaagta gngaatgagg agtgactgct aacaggtatg ggttttcttt naagggtgat 16980 gnnnantcta aaatcagatc attgctgatg gttgctgaag tctgtgaata tactaaaaat 17040 gattgatttg tatactttaa aagagtaaat gttatggtgt ataaatcata tctcaataaa 17100 gttgttacaa aaaagtaatt aactagccat gtttgttttt gtttttcttt gttttgtttt 17160 ttcatattgt caaggaattc ccagctttaa gtcacaatca agtgacaaag atagaactgg 17220 ggtggatgta tagtccatta ttaactacta cttcttactt ttctctagaa taaaggataa 17280 ctatgagagg atactataga aatcaatctt ttattcttaa aaggaccatt gctaattttt 17340 cactcacagt catctctggg attgaattcc atttatcaaa tcccttttat aagagctttt 17400 ctagctttta gtaatggact ggaataattt ttatttctta gaatttcttt ctcttagtca 17460 gatttaagtg taacctgctt tgcttattcg tccatgtgtt ccaagtcatg attttgctca 17520 ggacaaataa aatgctctac tagtatgagc ctggtagaaa gggaactacc atttaatgag 17580 gcctgtaatg tgtcagangc tccactgata tttcccatcc aatgcacaca acaaacctag 17640 gagcaggtat tantgtcatc tttttgaagg tgaagaagca ggctaataga ggtgaatgga 17700 ttgcccaaca tcacacagtc caaagttgca gaccccgaga aagcctgtgt tctttgctga 17760 acaccaggct accttccagc gttctcagtt ccgtgcaggt cagacggggt tcacttatct 17820 ttatggtcct ttatagctct ggtaaaaact aaaactgcca gactttggct acttggagag 17880 ttagttcaag gctgagggtg attttccaag tgcaatgcgt gatactcctc agcccaagaa 17940 ccacattttc caggctgatt ttctatgact cctaattaat tgttcaatat tcattcaaca 18000 atttgttaag cacccactgt gtgcctagca ctgtgcaaac actagtcatc taaaatatga 18060 ttatacggat tattcaggtt ttagaactct gtccttctgc tggagnatgg tgaggagggg 18120 gtgcctcttt cctctctagc caaagagcaa gggtgaagtg gcccagaaca gcgcccaccc 18180 cacccagggn tgctggcctc atgcatgcac atgtgcacat ctgtcctgta aagtatgctt 18240 gnccttgagc tttgtgaggg cagggnccat gtctttnttg tgccctacac anagcctggc 18300 ctggagcagg taggtgctna atgtcagttg aatcaatgat taagcaantt tttttttttt 18360 tttttttttt ttttttttna ccaattcact aggagaactt gggctggttg ctttattgct 18420 ctgtgccttc atttcctcat ttgtaaaaca aggataagag tacccatctc acatgccaac 18480 cctgagatcc cctgagataa tacacggcac tcagtgagca ctccacacac tgttactgtc 18540 tttcccatta ctccctttac tatagggagc catgggaagc ggcacatcct tctatgccaa 18600 gagtgacctc ctatccccta ttaccttgtc acctggattt ttgtttctta aattagagct 18660 gaaggccatg cggcccagct aaatggagct cactctgctc tgttgtgaga accttggtct 18720 gggaccctgc tgatgggaca gacatagtaa ccccgggagg ccccatcaga ggggcaggga 18780 gaggggaggt aagctatgtt tcagaaatgt taggatttga cttgaaagca cacccccaaa 18840 gcaatgccag ccagctcctt accaggacat ctgccattag cctctgagct ggtcatgtgt 18900 atgtatgtgt gtgtgcatgt atgtacaaac atgtgcaggg acccacaggg acaggtctgt 18960 cccatcaagg aaaacactgt ctcccactgg gcccnccatg tcactgttaa ccacagggag 19020 gttttgtggc cctggctagc ggagacccaa gacatatccc tcaaacctga agggcccagg 19080 ggcaggcagg nccggtttcc taagaaaagc cntttctaaa ggacccctct taggactggc 19140 agctgattta ctggactcta gcccttcgct ccaggtagaa cttcatctgc caatcctgtg 19200 tcctaatacc aggcccctca cagctttcca aaaagacact tgcggcacca taactcccca 19260 aaggagagcc cagccctaga atcaaccatg ggcagccatg cagtctagct gccttcccct 19320 gctggttgta agcagggtct ccaaaggcag atggcacccc tcatgggctt ggggcaaacg 19380 gccactgcgt gtgcatggct cttcctgtgc tgcatgatgc tgacagggct tcttgggccc 19440 ctcttcaggg agggaatggg accgaaagcc atcgatgcag agcctacagg aaggagaatg 19500 atgggagatg gccctcacct cacccccctt cccagtgtcc ccattcagaa ctcctgcatc 19560 tgcttcattt cctggaggcc aggtttgatc ccctgccagg gccagcttca tgggcatgca 19620 actgtgcagt cacacagagc gccacacttg gtttcaatgc tttgccattg ctgtattgaa 19680 attcttaata atttttgacc aaggagttct gcattttcag tttgccctgg accttgcaaa 19740 ttaagtagcc agttcccagt cctacccttt gctcatgcaa tgcctggctc cacatctaac 19800 agccttccnt tcctttctat ctctaaatcc tatctatcct gccctaaggc aaagtccaga 19860 cagaaaaata tttgacagac tacaaaggag agcacattat atttgaaaga gcttttctgc 19920 tcaactgcag atggaatgat gatggttggc atgttaatgc ctctaccaat cttgagttct 19980 tcttggctca gtctgaggct aaaggctgtg atggaggcct tctactccta gtcctgggta 20040 attgtctcct ggtatcacat tccttgaaga antgtagggc atcatattta ataagctcat 20100 tttgtcctgc cttagggagt ataggtccaa agcaggacac tggtacaaga ttgggttctg 20160 aggcccaagt aggtatctat catgctcatt tacttgctat gacttcagac aaatcccatt 20220 ctcacagtct cagtttaatc ttctgcaaaa tgggtcacac cacatcatga ggctttgggc 20280 ctcaattgct catctctcta agtcagaagc agaacccaag cttttatctg aagctttgga 20340 caattatttt tggagggaga tggccatgaa tgcaggcaca cgtcctgttt accacttccg 20400 gtctatggac tggcagaaca cattaatctg gccatacagt tttagaggat tcatttccct 20460 ttctcctgaa gcccatgcaa gagccccagg cgaggcaatc ctgctctggg tacagtctga 20520 gatttatcct tggattgtgc ctgagcagca gagcgctaac ttcctggccc gagttgtttt 20580 tcttctgcag agctgtgttg ggcnttgcct gtggccagca tttgagcact gtgacaggcg 20640 gcctcatgaa tcttgctatt gtctctagga caggactatt ctcgaggaca ttatcctcag 20700 catcacagag tggctccttt gtggaagaag tacataggag acacttcttt cngatctcag 20760 tattcagaac aactgtgctt ctgcgaataa gcagactact tcggatactg taacccttct 20820 gagagctgag ctgctgggat acgcagagcc agttttggag ccccgtctgg caancaggca 20880 ggcccgtgga caggatagtc tagggtcagt cttaccccag gcttggtttt tgcaacttcc 20940 ctcctcttta ttttccattt tccccaattc ccttagcttt ttgttttaca tttttctctt 21000 gtgtgtgtct ttataaacac ctctgtctgc tgcagaatna ggtgtgatat aaatatgtga 21060 gtttgtgctt aaatccacca cactttcaag ggagttgtga ggattcagaa ggaattgttt 21120 ggcgaatgca gtaaaagcag ccccatccaa gatggagcta gggctgggtg ggaggcaggg 21180 gtctttcctc cagactggat catctcgcca cagacagcag cccccaaaac ccaagcccaa 21240 agtgctcatt ggcatctgtt tgtttattta tttgttttta ataaatgaaa ggtcactaaa 21300 cacactttga aatttttgtc acctcccttg agatgttgct taattgactt aagtcaaact 21360 gaaactctgg ctgaaactca ttttgtagat gcactggcag ggacttgtta gggcagcagc 21420 atcccacaga ccctagggaa tgggagggac cacacttctg gaaagactgg atgggaagga 21480 gggtgtaggg atgtaggagg ggagctaggg agccctggag aggagtaagt aggccccaga 21540 acgatggggc cncgaatcag gccacaagct tggcctaggc gtgagtggac cagggaccac 21600 atgatttctc agaggggcct gctcagaaaa taaagtcaca gagctcctgg aaccnnntgc 21660 acttttcaac aagggnaaag aaattttacg cctggaccaa gtggccatgc cctctgccct 21720 gccntttggg nttttcaaac acctnccctc cgcactaggc tggcttctga agatgcagtg 21780 ccacctttac tttggactgc ctcacagctg aggggtcacc agtcacagcc atggccttgg 21840 ctggcttctt gctatgtaat gcgagcggag taggagcatc accctccctt tccaaagagg 21900 atcctgagtt tcagggaggn cagtgacctg ccccaggtta ctctccccag tcccgncaca 21960 ggccagtcaa acccagggct gcaaggccta tgccctttgt acaaaggcaa tatcctggcc 22020 caggggagga gagtctgccc gccagccgtg ctaatattcc ctcagagctg ggctggggtt 22080 gaggtctgcc tcagggttgn gntcacgctt catgctgtct tccttggcag tggaatctgg 22140 tgtgtgagga caactggaan gtgcccctca ccacctccct gttnttcgta ggcgtgctcc 22200 tcggctcntt cgtgtccggg cagctgtcag acaggtaagc acatgggagg ggaggaaggt 22260 gggatgntgc cccttgtcaa tcactgccta tcttggggct ggactgaatt cagggtattt 22320 ctacccnnnn naagggagga ccctcagncc actgattcag tgataggagg agccccgatg 22380 tctcntattc accccgccct cagtcccctt cacctggaca canttttgtt ccattctccc 22440 agcctcatgc tcccagggct ttggccagtg gtggggaggg gccactgacc ccactggaaa 22500 gtggggtcct cataccacag actccttgac aaaacatgac gctgccatca ccactgccct 22560 ccctgctcca ccaccacctc aggggtaggg gtggatggca caggatctgt ctgcaaacag 22620 ccagcagcca gacagtgagc cccaactgtg cacacactgc tgctgtggct tggaccctgg 22680 gcnaggcact ggggccacag agctgatgct ggctctgacc ctcatagagc ttacaggcct 22740 gaggaggcag catcacagca ccaggagaca gtattccaca ggcccctgta tgtgctgggt 22800 gaccagtgca ggaaggtggg ggtactaaat ggcaatgctg gggaaagcct cccagcccaa 22860 gccaacagcc agagacatga gtttggaaaa tggggcggga aaggctgttc tgctcacacc 22920 tgtgctccat tctatccact ggtcactacc agaatgtgaa gataatactt aaaacaactt 22980 cagtgtcacc aacagacatt gctgaaagct acaccttccc acagagcagt ggtttgcaat 23040 ttttgttgca cgctactcat ctgggaaact ttcccaaatc ctaataccca aactgtatcc 23100 caaaatcttg ggaggtgggg tgctggcatc agtatttttt ccaagctctc cgggtgattc 23160 caagtgcagc caaggttaaa aaccacttgc agagtgactc ttagttctgg atttacagaa 23220 ttttcatgtt gctgattcaa gaaatatctg caatctgtgc tgtacccact ttccagaaat 23280 gtgctggtag catctatctg tggctccttc taaagagcat atttccacaa ggtccttgng 23340 tacactgctc catgcttttg agacatggtg tctccacagg aagctgagaa tctcaaaaga 23400 tatctcctga gcagatggat gcntgagacc tcaccaagga ggaagatggg aggatgtgac 23460 agngaaaana gtctgccaga gccctgaaaa aacactaant ctgcattgat gcctgactca 23520 gggcttgcaa cacaccttgg caacctacac atctcatgtt ttgtgttata ctgcattctc 23580 taggtttggc aggaagaacg ttctcttcgc aaccatggct gtacagactg gcttcagctt 23640 cctgcagatt ttctccatca gctgggagat gttcactgtg ttatttgtca tcgtgggcat 23700 gggccagatc tccaactatg tggtagcctt catactaggt aggaatggct tctgggacat 23760 ggggtgcttc cctctaaccc tctgaaaggc ccagaaagag gaaatcattg ggccattggg 23820 ctgtgcttcc aaagcctttg gatatatgtg tcttgggagg gagccgtagc cacagctctt 23880 ggagcaagtc aggggcaggg caggcactcg cagggagcca cctctgtgct gagccctgaa 23940 atgtggtgga gaagaagagc aggagccatt aagaaccagc tgcacaacag ctgagacaca 24000 ttctctggag cacagggctt aagagaggca cagaggagga cagtttaggg gaagggcagc 24060 ctgaggatgt ctttgatctg agttgtgtag gcttgagact tcttcctggt tgcttgtgaa 24120 gagacttagg gtagtcactg tggccagtac acaggtgggg aggctcatgt cagacagggg 24180 gagttcagtg ccagcccncc atcactgggc ctatctggcc tcaccctgag ttagagccca 24240 ccccagagcc tatcagctaa gcacaggaca agcctcccca cactgatagc cccatctcct 24300 gtcaggctgc atgaggaaga ctcatcagtt acaaggtcat gaagaggtcc ctggggccct 24360 cagcagcttt tcctgggagg gagttaggtg agctccaggc gagttgatga gggtcatcca 24420 caggagtgag agagtgtgtt ctcttgagcc cagcgaatgg gcaaatgaga gaagcagagg 24480 tgaggggtat ccctgggaca gtagacacca gttcccatca tntctagggt gataatatat 24540 tctaggtggc tcagtaccat cccaatttgt ccctattgtc acagtgtcat tattaataat 24600 actcctttaa tagaagtcta acgattcttc ttgcctcaaa agtccgaatc tggttaggtg 24660 actctgattg ctttttaaga gtctgaagga ctcgttggct ttggagatgc tgcactgtct 24720 taattgatgg tgtgtacacc ttctgtcaag ttgccaggat ggaaatattc caactctact 24780 cctttaatta tttgcgaaga gccccgtgcc atgggctcag cctcagtgtc tgcagagggg 24840 agaagggagg agacaaggtg ggaagaacat gctggagcca catggtccca gcaggtagca 24900 cactcttcag caggccccag cgggaggagg ctgctcccct tcctgcaggg ggaaggagcg 24960 gggcaagatt ttcttgaaga tcatttgtgt agagggcaca gggagcttca ggccagtgtt 25020 gttggaaact ggaggttgga ggaacttaag atagaaattg caacctccta gtccccagtg 25080 gctccaagaa cacaaggcaa agcctattgt cttcatgttc aaagtcccca gaatccatct 25140 tccntgtgac gatcctccct aagcctgaaa aacccaacat gtggctctgc ttgggccaga 25200 cacataccaa aagccaaaca ggcctcccca aaacggagga ctctgaccag caggcccata 25260 tcccaggagg acctgaagga ccatctggaa cagaagggta gagagtcacg gtgaagccag 25320 agaagctctc tccgtgggaa tgggaacaag gtgggacttg tgccaggtgg tggcatcccc 25380 ggttctatag aatgggcagc actgagatct gcctttttag tggcacaggg tgattctgga 25440 gcctccaagc ctcccctntg tgagcgggtn aggcagggag agcatacccc aggcttccta 25500 caggaaaggg ctgccctccc ccgccggctc tgacactatc atctactctc ctcccagttc 25560 ccatgcagca tgtggtccca catgcagggt gaagaagggt aagagggcca aggggaaagt 25620 aaggccatgg aagatcagtc aagccagcca gtcagtaggt aagaccctgg gtgcagcagc 25680 ctcgctatca gctgggatcc aggcctctca gggcttgcta tcagcctggg gccaggcctg 25740 ttatagggtg ctctgggagc ctcttcatgg tagttttact ccattgtgct ctgcaggaaa 25800 ttactggctt ttgtatcctg gtatgagact cgttgtgttg gnttctcagg tctgaaagtt 25860 taagtgtccc tgaaaaccag cctgctctgg aatggctgga cgccccagtc agcacctggg 25920 gttgggggac acagtacaaa ggcaaggtgg ctgctagctt ccctacagtg cagcagtgct 25980 ctctggtgtt tctgggataa aatagctgaa ttccaggttg tatttgacta aaataaacca 26040 aagggtgtgg tctnggctga ggagtttggt aggtgccttc gcttccancc tctggcccta 26100 aggaagggtt ggcaaagctc tgcatgataa tttcacatta acttgggaag ccaaattact 26160 cccactgtca aagtagtgca gaaatgagtc cttgttttgt gctgctttta aaaaatgatc 26220 aaggctgcca cagtcgtagc agactagaaa agagaaagaa agaacagtgc taccctacac 26280 agcataaagc agacatgcct ggaagtgatg gtgttgccgg aatgatgctg gtttaggagg 26340 aaatgaccac tcgggaccaa ggacactaac cctacccacg ttccagctcc cctcacaatc 26400 tcctactgtt gcccagaaat aatgccctcc acctgtcaat agccttctgg gtagaatgcc 26460 atcagtatcc tctcttatcc cccataacta gctgcttaaa cacaaaaagt gtttctgtnt 26520 ttaataacac agaaaaaact cttgactgat tcattaattc agtatttttc agtacttcta 26580 acatcaacct ccatgtgaca tttctttggg catgctgaac catttaaagc tttgcttcct 26640 ctgatgtcta gaggttcctc cttttgatag gtgtgtaagt gatggcatct tcctttacaa 26700 ctctggctac caggaagctc aggcaaattt gaaatttaac tacatcaatg atgcagcttt 26760 taccagccac atatatatat attttttact gtttttaaat tgaacagttg aaatataatt 26820 ttgtcttcgc ctgtttagga tgccgtaaca aaatcctata ggctgggtgg tttaaacaac 26880 caaaatttat tttccacagt tgtggagggt agaagtccaa gatcaaagtg ccagcagggt 26940 tggtgtctgg tganggttct cccattgggt tgcanatggc tgccttctcc ctaagtcctc 27000 acatggtctt tcctcngcgc aagtgctcag aaagagggaa agcaagaaag agagagtgag 27060 ccatagagag ctcactctnt ggtgtctctt cnngtaagaa cactaatcct ataccctatc 27120 aggtcagggg atcaatgtat gaataataga gggacacaaa cattcagtcc atgacagatt 27180 tgcataccat gatattcaca cttttaaagt gtataattca gtggtgttta gcatattcac 27240 aaagttgtac agccatcaac actatctaac tcctcatcac cctgaaaaga aaccctatac 27300 gaattagcag tcatttccct cttcccctcg cccctggcaa ccactaattt actttctgcc 27360 tttaatggat ttccctattc cgcacatttg atataaacag aatcatatat tatgtggcct 27420 ttgtgactga ctccacttgt tttcaaggtt gatccatgtt gtaacatgaa ttagtattcc 27480 actggatgaa gacaacacat ttcggtcatc cattcatcag tcattgaaca cctgggtgtt 27540 tctactttgg ggctgttatg aataatgcta tgaacattgg agaataagta tttttgtgga 27600 tatatgtttt taattctctt gggtataagg taggacctct gctgggtcct atggtgattc 27660 tatatttaac cntttgagga actgccaaac tgttttcaaa atagtcagct gcgtattttt 27720 gatcttttca ccaaggcaca actttttact tttctttata tcttacttta atgttaccat 27780 tattttantg tatttaaatt tgaagttgcc tcaaaatctc caagggatga gctggcatat 27840 aaatacgtaa acatgatgca gaaatttgct ggcatacctt atttgcattg caccgtaaga 27900 gggaagaact ggggagaccc agggaagagc aagaacttac tcctgtctat tcacaaggag 27960 ctcactgcct ggttgtgcct ctgcagccaa tgcagctgtc actgtggaca tggggacatg 28020 ggtcaaggga gtggggcaca tattgctggg tatacacaga gataggaaat gttacttttg 28080 actggagtga ttggtgcaga cagaggggaa gccctgagca ggggaacatc tgttaagccc 28140 tgaagaggag ttctgtcttc cactgggcct ttttggatca aaagcattgt actttccatc 28200 antcccctga catgtagcac atttcaactg cttgatcagg ataaagaata actattactg 28260 agcacctgcc acatgccaga caccctccta ggcactttgc atacatgatc tcagtcttca 28320 taataatatc tccatgaaag acggcttatc acagtcactc tagtagcaac tcagcatcaa 28380 ggaacccagg ttctccccgt gccagatgga ggacactcct agcccatggt tcctgggtct 28440 cgcctcatat cctggcagct gcactacagt cttgtttctt gagctggggt ctactgagag 28500 cctatgttgg tcatttatga aggtgcatgt cctgcctctg tgtggaatgg gcccagcggt 28560 tcctggggca ggtactgctc tacatggaag gcagcctggc cctctctgag tcactccctc 28620 ttggagagag tgctcagatt cagaggggtg tgacaggtgg tgggcaatac tcctagggct 28680 atgctggccc tcatcctagc caggtcatgt ccctttggct tagatgtcaa agtttcactc 28740 ccaggagaaa ctcagaagcc cagccagacc aagaccaacc aggctttgcc ctagaagcaa 28800 agcaggcaga agaggcagat agagcatagg gggccaggac agggatcccc cgtcagcaca 28860 gcaggagtca ctgctgtgtc atctgtttca ctgccacatg gaaagctcat ggcagctgca 28920 ggccataaaa gatctgtgta atcagggttc tctcctagca ttactcagag gggtctggct 28980 ggcttccagt gacaagccaa ggaagggaaa atgtaaatcc acttntgaaa gggggataag 29040 gtgggtggat cacctgaggt caggagttca agaccagcct ggccaacatg gcaaaacccc 29100 gtctctacta aaaatacaaa aattagccgg gcatggtggc aagcgcctgt agtcctagct 29160 acttgggagg ctgaggcagg aaaatcgctt gaacccagga ggaagaggtt acagtaagct 29220 gagattgcac cnctgcactc tggcctaggc aacagagcac aagtctgtct caaaaaaaaa 29280 aaaaaaagaa aaaaaagaaa aactgtaaaa atgacagcag gatanggcct tacccatctc 29340 ccctcatgtc tntantggac tctcagttga agaactgctt tataaggcca agtcatgccc 29400 ccagtaattt ttttcttgga aggtagacca gtatccatag agcaaataag gcttaaatcc 29460 tggtgcacca cttattatgt gcatgaattt aagcaattgg ctttaactct gaagtctcag 29520 ctaattatgt gtaaagtagg aggaatatta gcttttgttt tagtttttgt ttttgtttga 29580 gatggagttt cgctcttgtt gcccagtctg gagtgcnnng gcntgatntc ggctnactgc 29640 aacctctgcc tcctgggttc aagcgattat cctgtctcan cctcccgaat agntgggatt 29700 acaggtgcct gccaccatgc ctggctaatt tttgtattct tagtagagac aggtttcatc 29760 atattggtca ggctggtctc aaactcctga cctcangtga tctgcctgcc ttggcntccc 29820 tantgctggg attacaggca taanccaccg tgcctggcct ggaatattag tttttatata 29880 actggtgtga agggtcaaag agataatata tgtaaacact tancctgnaa cctgtctcaa 29940 agtacctact caaaaaaatg ctanctgtga agatggtgat cctntttaag gaagggtgac 30000 tgcctaaaag agagcanaaa gtangactaa aaangantta tttcaatttg taccatccat 30060 gctgtccaca ggaaggcaaa gagagagacc tacaaagtct ctgtccccaa catgcactct 30120 gcaaagttat ataactgttc tggtctgaga cccatgctta gagagggaga ttatccagga 30180 acccagtagt ataacttctc ttttcttaac aaggtcatga aggtaggaga aagctcctct 30240 ggcctcacaa ttctacaaga ttctcacttg atcctgcgcc ctttctcttt tccaaaatca 30300 aaccctctgc cactgaatct ctgcttaaga ataaagcacc ttctatttat ttccacatca 30360 caatcacggc caaggggttt agaaaccagt gcatagcagg aaggtcatta atgaggtcag 30420 aaaagacctg gaaatcatac tcatgatcct caaagaagtc aggccctatc cttggaaatg 30480 ggtttatagg ctgagcaatg ctctgggtgg ttagggcaat tgtctccaac atgggatgca 30540 ggaggcacaa agtactggct gtttctatca gtccaggttt ttaaatggcc tcttgagagg 30600 gacccactga ggcagatctc tcagttatga acagtgaagg ggaatgagtg gggtgggatg 30660 ggaacagata ggtggtaaaa tgagaaacca gccaacatag taattttgct gcttctctgg 30720 aattagctct taatccctta gcctgtgcct agggcatata aacatgactg agaaaatctc 30780 tcttaaaagg cangcatgaa tgacctttga attatctgtt ttgtatcttc caggccactt 30840 ctctatagca tgggcagatc cccaacaaaa ggcagagcca ttgccattgg tcacatctcc 30900 gccccaggtg tagtgaacca agggcagact ctgtggaaag ggcccagagc tccgtgacaa 30960 gagaaggagc tttgtncttg gactcccatc tggtgccatc tctgctcact gtggcactga 31020 gcagagcaga ggccaatagt cgcctgcatg tcctttccca aaaagcagtg cccgcaccaa 31080 gcagtcatgg gcctttctgc tgttcaggga aagcactgtg agttcaatgg gtgtgtggac 31140 aggtctaggg ctgctgcctg caggggcagc agaacagcgc ctgcttttct ttccttggtc 31200 caaatggact gtggactgtg tctgcctggg ctgatctctg ggcacagcat gctgcaggaa 31260 ggcctgtctg tgnacctcca gagccagctc actccaactg atttctcagg gctcaggcat 31320 gggtaagtgt gccctgaggt cttggaaatg atgaactctc cactgcttcc tgatgggcca 31380 atgtctgttt atttacagtt cagaactgtt ggaaaggcta cacacacctt gaccccacat 31440 ggcccctcag aagagccact gcttgtctcc tgaaatgctc tctctgcttc tcatgttggg 31500 gctcttattt tggaaatgtg gcattctcag aagggattag ctcttggggc tgggcatgat 31560 atttttatga catggaatgg ccttaaaata agttggccag gcgcggtggc tcatgactgt 31620 aatcccaaca ttttgggagg ccaaggcagg tagatcactt gaggtcagga gttcaagacc 31680 agcctggcca acatggcgaa actctgtctc tactaaaaat acaaaaatta gccaggcgtg 31740 gtggtgcacg cctgtagttc cagctgttcg gaaggctgaa gtgggaaggt cacttgagct 31800 tgggaggcag aggttgcaat gagctgagat cacgccactg cactgcagcc cgggcaacag 31860 agggagactt tgtctcaaaa ataataataa taataataaa ttaattaaaa ataaataaat 31920 aaatctatgg ctccattaaa atctcataga aattcaacct tctataagtt gccaagtctt 31980 ggatcacgtc ccaccttcct ctaccctgac catgcctgct ctgggccatg aggcaaatgc 32040 ctttcccctt ttctaagtgg tgatagtttg aactctaact gccacataat gatataaaaa 32100 gcaaatatta aagtgagtta atatgctaat actcctccct tgttttgaac aggaacagaa 32160 attcttggca agtcagttcg tattatattc tctacattag gagtgtgcac attttttgca 32220 gttggctata tgctgctgcc actgtttgct tacttcatca gagactggcg gatgctgctg 32280 ctggcgctga cggtgccggg agtgctgtgt gtcccgctgt ggtggtgagt gtgactcgtc 32340 cccagacagg ccctctgctg cgggtcagca cacctggaac acacctggag cctgatgctg 32400 acctagcctg ggcttgcatg acctccacgg aactcgcgga ggccagcttc caagccggga 32460 gagtttttgc ctcattgtgg gtgggcctgt gtgctggagt ttgagtctcc attgtcctaa 32520 aaagcacatt ctcaggattc caatctcttc cttgatacca gccactcctg tctgttgcta 32580 cttgttattt gtggagctgg tggtgttgga ttttgttgtt tttaactctg ccccctgctc 32640 tttcatcact tttctctctc tagaaaaatc tcactctatc caactaatgt aattnttcaa 32700 gcttccctat catataacga ttagcatcta tgaaagggaa gcctatttat tagcactatg 32760 atagtgtgcc tatttatctg ctatgtctcg aagagtgaga aaattacttt ttatttaata 32820 aattgttaga gaaatgtcct cttctctccn cccncaacct cccaactcag ttttaacaca 32880 acagttatag gaataacaaa gtttgaagat tctggcctca gtcttgccca atatgactat 32940 ctgggggatt tcaggtgaaa gaataaatta aaaatcatag aacaaggtgt cagacatacc 33000 ctctttttgg agatttcctg ttcctttgct ttttcatatt taagcaagag aanaggagat 33060 tccttccatn ggtgggtctg gttctgtctc tctctcattc tctttctctc tcattaattc 33120 ttctttgttt gatttcatta tatcaaagtc aaatcttcca gcactgactg gtttcaccga 33180 actgcataac ttctacctgc ttacacataa cacaagcttc tttgaccatt ttttggaact 33240 cacaatttag actagacctc atggttgccc tgtcctttgg atacctcctg actgggaagc 33300 tgtctaggcc tttatcttac tgcagctgtt aggcagtcat agaggttgac aggcaggcca 33360 cctgtctgac gagatagcgc aggtcaggtg ggctcactct aagcccctgt attctcatga 33420 cctgtaagag tgctgtgatt tactagtgta aattattggc atgaagtgtg cagggggagt 33480 tgacagtttg ttaaaggtta tgtattattc tgatttgcaa cattcctctg gaaccctgtc 33540 tgaggaccng gaaacccggc ctgaggagca ntgaataagg gctggccatt atctacatag 33600 ctgtgcctcc aaggaaagca tcccagactt acaagagcag agcaattttc tgaatgagag 33660 taattatcat catcatcatc tgtccttctc tccacaactc ccttgctagc tgaatttatt 33720 ggaaaagatg ttagtgacta aggttctctc aagacacatg acaagattat tcaaaggttc 33780 ttttctgcct cttcagctga atggttttaa taaactatgt tctctggctc tagttgtcat 33840 tttgacctaa gagaccagta ctttcaaaat gttataatta gccaggtatg gtgnttcaca 33900 cctgtaatcc cagcactttg ggaggccaag gtgggaggat cactttagcc cagcagttca 33960 aaaccagcct gggcaacatg gcaaaaccct gtctgtacta aaaataaaaa attagctggg 34020 tgcagtggtg agcgcctgta gtcccagcta cttaggaggc agaggtggga gggtcccttg 34080 agcctgggag ttcaagatta cagtgngcta tatgatcatg ccactgcact ccagcccaga 34140 tagaatgaga tgctgtctca aaaaaaaagt tataatcaat ctgattaagg tatgattcta 34200 tcagagagaa agagagagag agaataacaa tataaagcct ctgatgggct gtacagagat 34260 tagtagggat gggatctttg cctcgggacc atatgtcaca gcgaggaacg aacagctctg 34320 atccattagc cctccagagt cagcctccag agtttccagc agagaaggtc catcccacag 34380 ggagcctgct cactntgccc taaggagagc tttttcttct attccccagg agctggtcca 34440 tgaatgctcc tggctgtggg catactgtac cagggacagg acttgcccca gacagaggcc 34500 agcctgggac cagcactgac aagctgagtg ctccccctga acatttacca gtggtcttac 34560 cattttccta taaaagaaaa tagctttctt ctgaacatcc catccttgca ggtgggtctt 34620 nccaaaggga tgctcatcan nctannggnt ggggtntgga gggatgctta gagctgacat 34680 ggaccctgcc gcctgctcag tatgagncaa gctctccagc aacacctcac tgctgtntag 34740 tctganttca atctacagag agattatagt gtgctacctc atttggcact ccattgactt 34800 ttgaaatgat cagctagatt tgagattatg tgcaccaaaa aaaaatcaaa gcaattcaaa 34860 actagagata ccagtggccc tgagtacagt gggctagaaa tgggaggtaa acctacatag 34920 aggcactgct ggtggtttgg gggacttttt atgtcccaag tttcctttaa aaggcttggc 34980 agtaagtggc cacaggtgtg aatggagtat gtgtataggc ggtggggatg gggtagggaa 35040 gcaggccata gatgcaatgt gaggaaagct atgcaatttc tagctgatta aacattaaga 35100 atctgaggcc agtggtctgt agaaaaaaag gtaggatatt tctaagcata atctggttgg 35160 agaaagatac tggccccatc catgaggtat atcgtggctg tgtagtaaga tctctaattc 35220 tgcactaata tagtagccac cagccacatg cagctattta agttaaaatt aattaaaagt 35280 aaataaaatt gaattttcat ttcttcaatc acactagctc aatagctaca tgtggttagt 35340 gggtgctgtc ttagtacaga tacagaacat ttcagaagtt tctatcggac agcacagttc 35400 taattactga gagtcagtga cctaacatta tngtagttcc tatagggacc cactaaaggc 35460 atattctgaa aaatgcaaac taggctcatt tttcaactca tgtgctatta agctggagag 35520 gggacctgct ggttggtcat ttgttttgct ctgagctaat tcctagtgtg ggtttggggc 35580 caattaacta cacaggactc tgtgtctgct acttataatt tgttntctag gctaagtaag 35640 tacagatgct ctttgactta taatggggtt acatcccaat aagcccattg taaattgaga 35700 atattctagg tcaatacacc taacctactg aggtaggagg ccagacacga ctccagaggc 35760 agggcttgga cactggacca aattgaggac cagctaaaac anagccaggg cagaagacgc 35820 tttccataag acacgcccac ccgtgtgcca tgtcagttta ctgttgccat gacaacactc 35880 aggctttatt gcccctttcc atggcaatga cccaatgacc caaaaattac taccctttcc 35940 ctagaaattt ctgcataaac tgacctttca tctacatgta attaaaagta gttataaata 36000 tgagtgcaaa actgtcctga gctgctactc tctgcctgtg gggcagccct gctctgcagg 36060 agcagtcacg gagctgtaac attgcntctt caataaagct gttttcttcc acctccagtt 36120 tgcccttgaa ttctttcctg ggcaaagcca agaaccctca tgggccaaac cccactctgg 36180 agcttgcctg ccctgcatcc ctaccaaata tcatagctca gcctgaccta ccttaaacat 36240 gctcagaaca cttacattag cctacaatng ggcaaaattt tctaacacaa aacctatttt 36300 ataattaagt gttgaatatt tcatgtaatt tattaaatac tgtactgaaa gtgaacaaca 36360 gaatggctgt atgtatgagc actcaaagta aggtttctac tcaatgcata tcatttttct 36420 cctatagtag aaaaatcata agtcgaacca tcataagtta gggaccatct gtactgacaa 36480 taggtaagga aaatgagagc tgacaggaga atggctaaaa gattttgaga aataaaaatt 36540 tagaaagaat agaagcccta ttatttgcaa ctgtgtttga gcatcagcta taaatgggaa 36600 tagactatgt aatttaaaac aataagcttt tttagacatt aacaaaaaga caacattggg 36660 gctcatctcc caaaagctgg tttgggcact cgctgatctg ggaatctgtt gaaagccatg 36720 ggggccccac acaggngggt gtcagtgccc tcactttctc ttttgactaa aggaaacgat 36780 cangaacaca ggtgccctgg ccatcctttt cccaataaac tgtgaacatc accagctggg 36840 acaccagcaa ttctccttag gatggaccca ctgcaaagac agtctcttct ctaggggaac 36900 ttatagtcta gtagctatgt ttcttttatg agccacacta cctataagtt ttggatgaac 36960 ttctccagag ccctggctca aacatgccca tagttaatgt caccccttat ggtctggtcc 37020 tggtctcaag cacaactgat gatcggtctt ataatttgat cagaagtttg aaacttgaag 37080 gtggttttat ttattcctat gctccaatag aaatcttatg tggactccct ttaaaaagac 37140 aaactagaat tttacaaaat taaaactatt tgggggaaac tcagatttaa tagtatccag 37200 ccctgctgtt gtgaaaaatt attaaatatt aaaaataaat tataggttca ttcctgaatc 37260 tccccgatgg ctgatatccc agagaagatt tagagaggct gaagatatca tccaaaaagc 37320 tgcaaaaatg aacaacanag ctgtaccagc agtgatattt gattctgtgg aggtaagcat 37380 ttgcagatgt ttcctcttga gatcagctat gcattcttga ttttatggaa tttaacttaa 37440 ttcaatattt gttaanngcc cactatgtac caggcattgc actaggcctt aggaacacaa 37500 tcatgattaa attctaagat aaaatccacc ttaaagggct gtttataaga attaaatgca 37560 ataatatatg taaactgctt agcaaatagc aagcgttcat taaatattag tttgctttat 37620 tttgcaagtt tatcatcaac tttctattgg cattgctcca aaccactgac acagctatgt 37680 actgatgatt tttaaatgtc cagattaagt ggaaaaatat gtttcagggc tagtccaccc 37740 tgggttctcc actgtaccct gaatcttacc acagactgct gaggaagcta tgcatgtctt 37800 tagtctcact ctgtgtcatg tctagaacct taaggcctga aagcacaggc ttgaggattc 37860 acccttgaaa gctggtggcc acaaggaaaa gctgatattc tgtggaagca gccncacctc 37920 ctgacagttc gtgaggatat gcagtgtgcc atgccctgtg ctggctccta gaggaaataa 37980 gaaaagacac agcccaaatt ctaaaggaac atagaatgta actaagattg gcaagaggat 38040 tagataaaaa gataaagaat ggcataaggg aggaaatggt aagtatccaa gtagagacac 38100 tgtgtgccag caatacagag aaagatagca gggtggccca tggctggagg caggtccaag 38160 ccagggagga cagcaggact cacttaaatg agtggagagg atggggcagg gcattcctgt 38220 ctaggagata ggtaggagtc tgctcaggac acctaaaaaa gactgtggtg gcttcagtaa 38280 cattatacat gccctgcacc aaagcatgta gtacagaaag cagaactctg tagaggacgg 38340 tgggcatgcc actgctcacc cccacggctt ccccagtccc tggccttcag gaccttttcc 38400 agaagcagat actctggcta tggctagagg cttagactgg ccatgaactc aagctctcag 38460 agggctgcca ggacaaaaca tcccttaatc ctttgccctt caaatcaaga agtccatttc 38520 aagtctcagt caatttaaat ggataaaaca acaacaacaa caacaacatt gggagtgtct 38580 aacacttctg cccttcaggg ctgtgctggg gtgtttatng gtatttatca gctaggtggc 38640 ctgattccta tctgtgaaac ttanagtcta gttgtaggga tctacctatg tggatgacag 38700 caatcataaa atagatatga gatatatagt tatggacaaa taagaatata gttcagtgtt 38760 aaaacacatg gttctggcag tgccttnana nacacacaca cacacacnca nanananann 38820 nnnannnata tntnnntntn tntatatatn tntntntnta tntntatata tanananaca 38880 cactttaaaa aaattttgag tctcactgtt ttgctcaggc tagagtgcag tggtacaatt 38940 acagctcaat gtagcctcga cctcgacctt ctgggctcaa gcaatcctcc cacctcaacc 39000 tcccaagctg ggactacagg cacttgccac caaacccagc taacattttg tatttttttt 39060 tgtagagaca gggtttcact atgttgccca ggctggtctc aaactcctgg gctcaagcaa 39120 tcctcctacc tcagcctccc ataatgctag gattacagat gtgagccatc attctcagcc 39180 tgacagtgcc ttctttcttc ctgccatgat gcacatctag cctgaactgg acaaacccat 39240 taagggaaag ggggcttgcg ctttcctgag gcctggtcat ctcccctgct cacctcccgt 39300 aggatcctct ttaggaggat ctgcagagcc ctgtgccagc aaatgcaccc tatttagaat 39360 gatattgaag agcctaccaa atgccaggca ctgtgttctg ctcattgctc atgctttttt 39420 ttttttnnaa aaaannaann nangnnnnag cgaagttaag taacttgccc aggatcacac 39480 agatgttaaa ctgggatttg tgacctagtt ctcccaggca ccaaagtaca tgctcttaac 39540 aactgtgatt tttcacttca tgttacaggc agtagcatta acttggatag gaaaagatat 39600 agagtagagt attgtcttag aaagcnatct caagcatcct tggcttcana agaagcacct 39660 tcaacctgct nctggtacct gatccaaaga cattttggtg gctccaccca ggccagggac 39720 aaccactgga tacaagcata ttcttgttct gaggtttcca atcctggctg ctcatcacaa 39780 tcacccaagt gctttaagaa tacagattct caggcctctg tttaaaagag tcgaagtagg 39840 caagcccagg gaggaacctg gcaacctgca tttaagaagg gccccgtgga accaccaagt 39900 attagcacag gactggtcca caggtcctgt ctgtgtgcac caccctggaa ccctccaaga 39960 ngatgtctgg ttcccactag tttatgcagt ggctttgctt tgttataata ccagggttat 40020 tctgctgggg gcatgttctg gggctctaca atccaaatag tgcaagagag aaaaggcaat 40080 gtggctgnga gctgtgtaag tgtctgatca ttcctagaaa aaaggacact cacatttgga 40140 gaggacctgc tgtgaaggca ggcctggcac tcccacttct tcataataaa aactcctcca 40200 tcagtctctt actgcgcatg cactgtaggg ccacaaagtc acaaagtcct ggtacttcat 40260 ccctgagaga ttccccacct cagagcctaa taacttttat gttagtttca attctaatca 40320 gcttggttac cttgattcat aactcatagc aagttaatat cagcaaatta aaagcaaaag 40380 aataggccgg gcgcagtggc tcacacctgt aatcccagca ctttgggaag ctgaggtgga 40440 tggatcacct gaagtcagga gtttgagacc agcctggcca atatggcgaa accccatctc 40500 tactaaaaat acaaaaatta gccaggtgtg gtggcaggtg cctgtaatcc cagctactca 40560 ggaggctgag gcaggggaat tgcttgaacc tgggaggcgg angttgcagt gagctgagat 40620 cgcgccactg tactccagcc tgggcaacaa gantgaaact ccctctcaaa aaacaaacaa 40680 gaaaataaat ataaataaaa gtaaaagagt ataaacccat tgatagcagt aaggatttgt 40740 cactgaccgc tgatggctag cctcttttcc tcaatgatac agtaataata ataatagttt 40800 aaatttactg gacatttacc atggttcaag cactgtgcta agctatatat atatgatctc 40860 atttaatctc tcaactccca attaatatac ccattttata tagcagtaag ctgaagttca 40920 gagaggatcg ttacttgccc aaggcccgcc agtaaactga agtctgttct gatgctaaat 40980 gactacaaca agagaagtgt aaaaagcaag gctgggtaat cccagcactt tgggaggcca 41040 aagtgggcag actgcttgag gccaggagtt tgagaccaac ctggccaaca tggtgaaacc 41100 cagtctctac aaaaaatgca aaaattagcc agatgcggtg gtgctcgcct gtaatcccag 41160 ctactcagga ggctgagagg caggagaatc gcttgaacct gggaggtgga ggttgcagtg 41220 agctgagatc acaccactgc actccagcct gggccacaga gctagactcc atctaaaaaa 41280 aacaaacaaa taaacagaga agtgtaaaaa gcagacgtgg cctcaaggaa gggactacat 41340 ggccctaccc ttcaataggc agtcctgagg atcacagatc agtgtggtaa atgacatcca 41400 ttctctgact gtcagtcaga gaaaggctat gttagccaac aggctttgtc taacgagaca 41460 gggaaggggg tgttatatat ttaaaaggct tctgtgtaaa atggactaca aacattttaa 41520 agtgtcagag taagtgtcat atatgtagat gccctattgc ctccaatcac cagacttcta 41580 agcatagtca aggtgaagtg ngagttgcat gcataagttt tccccatgca tcatagccaa 41640 agatacttcc ttactacctc ttaatctcat ggttatttgc attattttgg ttacaggagc 41700 taaatcccct gaagcagcag aaagctttca ttctggacct gttcaggact cggaatattg 41760 ccataatgac cattatgtct ttgctgctat ggtaantaat aagtgacctg gaaatgcaga 41820 tatccagcac ataagtatgc aactgatttn cttaactcag agnaacatta tgacaacgac 41880 tgggttntcc tgaggaaaaa ttaagattat aaaattctaa attattttga aatgcctcta 41940 ttcagttcat gggactagat attgaaaaat gtcactgggc gcantggctt acgcctgtaa 42000 ttccagcact ttgggaggcc aaggtgggca gatcacctga ggtcaggagt tcgagacgaa 42060 tctagccaac atggtgaaac cccgtctcta ctaaaaatac aaaaattacc tggncatggt 42120 ggcacatacc tgtaatccca gctacttggg aggctgaggc aggagaatca cttgaaccca 42180 ggaggtggag gttccagtga gccttgatcg cactactgta ctccagcctg ggcagcagag 42240 caagactcca tctaaaaaaa aaaaagtcac agggtacagt atttaagtct gcagtactgg 42300 gacccaaagg gaaagcattc ccttccccct cctaaagtta tgggattgag atcattgatg 42360 tccctgggta atggttccct ccccaccaaa aattatgaga ttaagactaa tgatgtccgt 42420 gttgcctgag gcaganatgc taattcagct cctgcttcct gaagctgacc tggcaattga 42480 acactgaggc tagaataacc tagatcccca ttgcctggat tggagccttg atcagctttt 42540 tacacgtgcc aatagcaaac taacaagtgg ctttcaggcg cagaaatact gaattggctt 42600 tatagattag atttaataat ttatctgccn nnaaaaaagg aaaaaagaaa antcctactc 42660 tatgatggca gcacacacac acacacacac acacacacac acacacacga tgatngtcag 42720 aactggtaga tttaggctgc agctaatcta agtttatttt taagggccat cctacttggc 42780 aattagaaga gatcaatgac agagcttatg cgtctgaatt aagcaagtgt gtcctaggta 42840 catgggcttn ttagttctta catttcagcc tatatccctg atgcaaatgt tcttgggtag 42900 tngtgctact aagctaataa aaaattagtc actagttcta tctaanctac tcctattact 42960 aaatgggaaa atcactaaga tcccttgagc atacttattt gttgtgttta tgaattagtc 43020 cttgtattat ctaatttggg tctagtatgt gtaaaaagat ccactagtgt tcctgaagtc 43080 atttttcaga tatcctctgc ttctcagtca tgttaataat aagcaaattt ctacacaggg 43140 gtgtctgcat agtgcagttg taacaaaaac tcaggttcag tcactcacag cttgcagcgt 43200 ccaattaaca agagcaaagt ctgatgtaag gaaagtgact ttttattcca aagctagctt 43260 agggagaaag gtatcggctt cctgcctgaa gggtaccacc gctcctcttt ttgaagcgga 43320 aagcaggcac ttctaaaagg caggggagga cgcgagcagg tgagggatca ganggctagc 43380 ttgctgcctt atctactggg cagttgannt ggtgccttca tgggcagaaa caggttgtat 43440 aggtggccaa aaactctagc aggcatactt tgagttggaa attgactgat atcgcttgag 43500 gaaatctggg cngtgagagt tccactctgg agcttctaag cacatagtta gatgaatttg 43560 ccctgcaggg agtgtccagt gaagaggagg ttaaaaggct ataattgcac ttctaaagag 43620 ctaagtagaa agtgcagaaa aggaggaaag agaaaangag agagaaaata aactatctct 43680 tagaaaaatg ggggtactca gttacatagt tatttttcca cagagaagct tctttttttt 43740 atttatgttt ttattttttt gaganagagt ttcgctntgt cacccagcct ggagtgcaat 43800 ggtgcgatct cagctcactg caacnttcgc ctcctgggtt caagcaattc tcctgtctca 43860 gcctcccaag tagctgggat tataggcaca tgccaccacc atgcntggct aatttttgtc 43920 ttttaagtag aganggggtt tcaccatgtt ggccaggctg gtctcaaact cctgacctca 43980 ggtgatttgc ctgcctcggt ctcccaaagt gctgggattt caggcatgag ccaccacgca 44040 tggcccacag agaagcttct acatggaagt taactataat gacagaatat acagactgca 44100 gtctgtgata ctttgaagga ttaggggaca ttcactcttt tccctaaaga gaatcagaat 44160 ttattctaag tgaatcccac agtatgaccc ttgtatctct tttttgttaa agaatgaaat 44220 ctggatttta tgttcactga tgtgactaat attttttctt catataatag ctctaagaga 44280 ttgaggaggt acaaactatt caggaaatag gaaaacttga aatcaactag ctgagaaaag 44340 ttattgttga atattggtat atctagacta gcactgtccn atagaacttt ctgcagtgac 44400 ggaaatgttt catatctatg tngttcaata tagtagccac tagctacacg tggctattga 44460 gcacttgaag tgtggctagt gtaactaagg aactgaattt gtaatcttat ttaattttaa 44520 tttattcaaa tttaagtagc caatgagggt agtggctant tataagacag caagatatag 44580 agaatttctt gaccatcata aaattttaga gcgattcaca ccatcccttt gtcattttta 44640 ccttcttctt tcaggatgct gacctcagtg ggttactttg ctctgtctct ggatgctcct 44700 aatttacatg gagatgccta cctgaactgt ttcctctctg ccttgattga aattccagct 44760 tacattacag cctggctgct attgcgaacn ctgcccaggc gttatatcat agctgcagta 44820 ctgttctggg gaggaggtgt gcttctcttc attcaactgg tacctgtggg taagaagtta 44880 accaagatga acagcttacc agaaaagacc cacatattga ctaggctgct tctgagtcac 44940 tgctccatgt ttattcagcc tttacatcat aagccattca taagtcaatt agacaggtga 45000 ttgctcacta cgtatgttgt ttcctgtgtt caaaacaact accccaaaca gaagagacag 45060 tctcagagaa gcagaaagca ccaaagagga agagtaactc tcccagtcat ccccttcaca 45120 gaannactca cctaacatct ccctttaact catantnntg attcctaatt tntggctact 45180 ctcaaacatt ttccctgggt gtatattcaa gtattacagt gagtaggaca tgtcggttcc 45240 aggatacatt cagtggtttt ctggtctgaa tctttaagta gttaaatagc acacaaaagg 45300 atatatgctt cccttttccc cttgtgtctg acgttctcat aatattaaaa tgtcactaaa 45360 ttattgatag taatagaaat acatatttct taataataag aaagaggata gaaaggattg 45420 gtcctcctct ttgaagataa aacttaacta tattaacatg ctaatagntt acccatgaaa 45480 ctgttttaac aaacaaaaga caagtggaca aaggtcactg aatgcattaa tgacctagaa 45540 taacagtaga acaaagtaca aagccacccc tcacatgagc tccatctttg tccatgccca 45600 aatattagga catttgaaga gaaaatgcta ttttgggaat atatttatgt taataaaagt 45660 actcccactg aagcaaaaag gacaataaaa ataactgata taagaaagta tcanttctaa 45720 aagcaccatt gtttataccg ggtctctttt ccagattatt acttcttatc cattggtctg 45780 gtcatgctgg gaaaatttgg gatcacctct gctttctcca tgctgtatgt cttcactgct 45840 gagctctacc caaccctggt caggaacatg gcggtggggg tcacatccac ggcctccaga 45900 gtgggcagca tcattgcccc ctactttgtt tacctcggtg agctgcatct tgtgcatttg 45960 ttcttccttt aaattagttt tcaatgntaa aagtaagatt ttcattgtga aaacgtcaaa 46020 tagcatagaa tgtacnggaa anaaagtaca agttcncctc tcctctccca ggaggagctc 46080 tagaaagccn atcncaaact ggtgagtagn gntncagaca ntttgttttg cacnacatca 46140 tgtncncang tatgtatata attttttaaa cacacnngca actcaggcgt ggtggctcan 46200 gcatgtaatc ccagcacttt ggnaggccaa ggtaggtgga tcacctgagg ccaggagttc 46260 aagaccagcc tggccagcat ggtgaaaccc tgtctctact aaaaataaaa aaattagcca 46320 ggtgtgctgg caggtgcctg taatcccggc tactctggag gctgaggtag gagaattgct 46380 tgaacccagg aggcagaggc tgcagtgagt caagattgca ccactgcact ccaacctggg 46440 caacaanagc aaaactctgt ctcaaaaata aataaaaata ataaaaaata aaaagaataa 46500 acacacaaat aacattatat atgttaaaac tttttaaact taacattgta tcagaatatc 46560 cttccaaata gttacatatt gctcctttac cttcttttta aataggtacc tccttttaaa 46620 aatgtatata agtacatttt aaaataagta tatgtaagta taatctacag atagattcac 46680 agaagtaaaa ttcctggagc aaagagtgcc gtntaaaaaa ttatatatat atgtgtgtgt 46740 gtacataatg ttgtgcaaaa caaaatgtct gtagggctac tcaccaaaca gttcatgttg 46800 gttttctagg gatcctcctg ggagagggga ggtgaacttg tacttttttc cagtacattc 46860 catgccattt gaagttttca caatgnaaaa tcttactttt atactngaaa cacataattt 46920 atttaaccag gctccaatga atggaggaca tgtaggtcat ttccaggttt ttgctattac 46980 aaataancat tacaacgaac attctnccta tgctcctaca ccctttgtga atttacttac 47040 gtatatttgg atttacaggt agattcatag aagtaaaatt cctggagcaa agagagccat 47100 taaaaaattt catagatatt cccaaattga actctacata ttgtgccaat tataatctaa 47160 ttattaatag gtaagagtgg ttttcaataa tctcaccaac aataaagatt acctaattct 47220 tttttttttt tttttttctg agacagggtc tcactctgga gtgtagtggt gcgatcctag 47280 attcccagct cactgcagcc tcaatccccc aggctcaaga gatcctccca cctcagactc 47340 ccaactagct ggaactacag gcatgcacac cgtcaagccc agctaatttt tttttttttc 47400 tggtanagac gggattttgc cagtttgccc aggctggttt cnaactcctg ggctcaagtg 47460 atccacccgc ctcaacctcc caaagtgctg ggattacagg tttgagccac agcacctggc 47520 ctaatttttt aatcattggt tatctgttat gtgaaaaatg gatatcattg ttactttcat 47580 tcctatttat taattatgaa tgaggttgag catgtttttg tgtatttttt ggccatttta 47640 tttatttttc agtgaactga ctgctcatgt tctttgcccc tttttttttt tttggagatg 47700 gagtctcact ctgtcaccca ggctggagnt acagtggcgc aatctcagct cactgcaacc 47760 tccgccgcct gggttcaatc aattctcctg cctcaacctc ctgagttgct gggactacag 47820 gcgcatgcca ccatgtccgg ctaatttttt nttttttttt gtatttttag tagagatggg 47880 gtttcatcat attggtcagg ctggtctcaa acccctgacc tcaggtgatc cacctgcctt 47940 ggcctcccaa agtgctggga taacagacat gagccactgt gcctggcctt ctttgcccat 48000 tctttaatgg tgtatatcgg gcaaaattca gccctgataa ttcacatagg nttcttttct 48060 attttcccta agtgccagct ggtctgagaa ataaagggac agagtacaaa agagagaaat 48120 tttaaagcta ggtgtccggg ggagacatca catattggca ggttccatga tgccccctga 48180 gccataaaac cagcaagttt ttattagtga tttcaaaagg ggagggagtg tacgaatagg 48240 gtgtaggtca cagagatcac gtgcttcaca aggtaataga atatcacaag gcaaatggag 48300 gcagggtgag atcacaggac cacaggaccg gggcaaaatt aaaattgcta atgaagtttt 48360 gggcacgcat tgtcattgat aacatcttat caggaaacag ggtttgagag cagacaaccg 48420 gtctgaccaa aatttattag gtgggaattt cctcatccta acaagcctgg gagtgctacg 48480 ggagactggg gcttatttca tccctacagc tncaaccgta aaagacagct gcccccaaag 48540 tggccatttt agaggcctac cctcagggac gaattgtctt tctcagggat gttccttgct 48600 gagaaaaaga attcagcgat atttctccca tttacttttg aaagaagaga aatatggctc 48660 tgttctgccc gactcaccag cggtcagagt ttaaggttat ctctcttgtt ccctgaacat 48720 tgctgttatc ctgttctttt ttcaaggtgc ccagatttcg tattgttcaa acacacatgc 48780 tctacaaaca atttgtgcag ttaacgcaat catcacaggg tcctgaggcg acatacatcc 48840 tcctcagctt atgaagatga cgggattaag agattaaaga caggcatagg aaatcacaag 48900 ggtgttgatt ggggaagtga taagtgtcca tgaaatcttc acaatttatg ttcagagatt 48960 gcagtaaaga caggcgtaag aaattataaa agtattaatt tggggaacta ataaatgtcc 49020 atgaaatctt cacaatccac attcttctgc catggcttca gccagtccct cctttcgggg 49080 tccctaactt cctgcaacag gtgtattcat ctttttcttt ttgacttgtg caaactcttt 49140 gcaatggaag aaattagccc cttgtatata tgttgtaaat atttttccta gtttaccatt 49200 tgtattttca ctttatgata tctttgtaat gaagacaatt ttagttttta tatactcaaa 49260 ggtgtcaatc tgaaatgaaa ctacagaggt gtttcagcgg catgttcaat ctgatgtagg 49320 atctgacacc ccatgcctgg tcctcattaa ggactctact ggtgagaaat gcagacacac 49380 ctcatcaatt gggcaattgg ttacctactg gtacacacgt acacacacac acacacacac 49440 acacacacct gaaaacatgt atgaattctc aggaaaggta taatccaaac ccttacagag 49500 aaagagaaac attttcctaa caaacatatt ctgcacagtt gccctgtgcc acacctgaga 49560 tagcagatta tacagagtgg tgttattttt ccctttgtcc ttccctgtac tttcaaacta 49620 tttcaaacta tgctcagatg gtccagtggt cagacactgg tacataagac agggagtcca 49680 agagtctcct actccacaca gctactcctg ttagtgacac agaggcctca gagaagctgc 49740 aataacaata ttttccttat gttttgggtc aaatgaaatc catgggtgtg ctgttcctct 49800 gtaagctctg tatgtataca ggggcaaagc aagatgagga tctgtttttc tcctgtgtga 49860 gtaaagcttc acaaagagat tacatattaa cccaagacat gtaagtgctc caaaaagaag 49920 ccaaatccag gcacacagtg cctttacaga atgtgcctga tacttataat ttactgattt 49980 aatctgaagt gaacataata cttagttgtt tttttttttt tttttttttt ttttgagtct 50040 catagccctg tggacctaac tttccactgc agcctactag tttgggcaaa agcagagtca 50100 tgccagacct atcatngcca aaacctatcc ctgaaacatc ctggttaacc tccttctcct 50160 tgatgtcctc ccatccccca tttccaatta cctccacctt aagaggagaa ctctggtagg 50220 caaagaactc taccaaagga acatctgtca cacatgactg agtagtagct tagaggatac 50280 cagttgacag gaaagaatga aaagccttat gataatgcaa aaggattata gacatgcaca 50340 atgtcatctg ccaaaaagaa actgatattt tgcttacttt tttttctctg aaaatgttca 50400 gatttaaatc cattctctta tactgttcac caacttcaca aaatgatgct caagagtgcc 50460 cagagagtcc tcctatctga ttgatgttct tatgtcccgg gctttacagg tgcttacaac 50520 agaatgctgc cctacatcgt catgggtagt ctgactgtcc tgattggaat cytcaccctt 50580 tttttccctg aaagtttggg aatgactctt ccagaaacct tagagcagat gcagaaagtg 50640 aaatggtaag taggactttt aacaaaatga taccaaaatg ccttagggag aataagcatg 50700 gaagaatagc taggaaggtt ctgaaataga agagtaataa gtagagacta gctctatcag 50760 ataataaagc atattgttgg ctgggcacnn ngnnnnncnc nnntnnnnnc nnnncnntnn 50820 gngnggctga ggcaggtgga tcacctgagg tcaggaattt gagaccagcc tggccaacat 50880 agtgaaacct catctttact aaaaatacaa aaaattagct gggtgtggtg gcagtcncat 50940 gtaatcccag ctactcagga ggctgaggca ggagaactgc ttgacccagg aggcagaggt 51000 tgcagtgagc tgagatcaca ccactgcact ccagcctggg caacaagagc aaaactccgt 51060 ctcaaaaaaa ataaataaat aataggccag gcgcggtggc acatgcctgt aatcccaaca 51120 ctttgggagg ctgaggcagg cggatcatga ggtcaagaga tcgagaccat cctggccaac 51180 atggtgaaac cctgtctcta ctaaaaatac aaaaattagc tgggcatggt ggcacacacc 51240 tgtagtccca gctactcagg aggctgaggt aggagaattg cttgaacccg ggaggtggag 51300 nttgcagtga gccaacatca tgccacngca ctccagactg ggcaacagag ctagactctg 51360 tctcaaaaat aataataata gtaataaagc atattgttga gcaatagtaa ttaaaacaat 51420 gtgataatgg tataggaata gaaaccaatg gaataggata gagttcagga taaaacccaa 51480 gaaaatataa aaattcagta tgtaataaaa agtagcaaag tcaaggggga atagttattc 51540 agtaaaaggt attagaacat tcagctagac attttgaata aattaaaaag ttgtctcttt 51600 aaaaaatgca ttggctgggc atggtggctc acacctgtaa tcccagcact tagggagatt 51660 gaggcaggca gattgcttga ggtcaggagt tcgagaacag tctgtccaac atggtgaaac 51720 cccatctcta ctaaaaatac aaaaattagc caggcatggt ggcgcacccc tgtaatccca 51780 gctcgcggga ggctgaggca ggagaatcgc ttgaaccagg gtggtggatg ttgcagtgag 51840 ccgaaatcgc gccactacac tccagtctgc gtgacagagc gagactccgt ctccanaaaa 51900 aaaacacatc aagataaaat ccagacagtt aaaaaattta ggcctaaaaa tgtaaaatca 51960 taaatatacc aggaggaaac aaacattttt ataaccttag agaagatctt actgagcata 52020 acataaaatc aaagaaccat aaaggaacag attgatatat ctgattgtac attttttaaa 52080 ttattggcaa ggcaaaaaga aaccacccac aaagacaaaa gtcaataagc caggagaaaa 52140 tatttgctac acaaaaccta aacataaggc taatatactt aatatacaaa aagctcatag 52200 taaccagtga gaaaaagaca aacaattcag taggaaaacc agcaaaggac aagaacagac 52260 agtttacaga agaagtcact tcagtgtcca atatatacat gaaaaaagtt atttgtccac 52320 attaataagg aaatgcaaaa ataaaacaat tcaacatctt tttttggctt atgagattgc 52380 gcaagggttt ttcttcttga cgcaaaccaa ttctgacacc tattgagtgt cctataatgc 52440 agtncaattt tgacaatacc taaatttagc atcagactcc acaggtgtaa agactcagtc 52500 ccacaatact gccttgcttc acttgccact cacaaatgtc aggtccccag gttacccaca 52560 tttctctctg actttgctac caagtctggg gttccaacaa atcccctcct tgggtttgat 52620 tatttgctag aatgactcac agcactcaga acactggcca ctagcngttt cttacaaagg 52680 atacaaatga acagccagat gaagaggtac atacagagag gtctggaagg gtcctgagtg 52740 cagaggttct gtccctacgg agttaaggtg cactgccctc ctggcatgtg gatgtggtca 52800 ccaactcgga agttctccaa accccatcat ttagaggttt tcatggaggt ttagtcatgt 52860 tggcatgatg gattattaag tctatcccca gcctctctcc tctccccaga ggttccaggc 52920 ttctaatcca ggcttagtct tctggtgacc agcccccacc ctgaagctat ctaagggccc 52980 agccaagggt tgcctcatta gaacaaaaga agcttttatc actccctatc actccagaaa 53040 ttataagaga tttaggatct ctatgttagg agccagggac aaagaccagt atctttttat 53100 gacaccacag caaacattta aaagattagt ggtatttagg agaagtttag agtttcgagt 53160 aacactgcct ggctttaaat cccaaatcta ctgcaaaaat ttgggcatat cacttaatat 53220 tcactaagct tcagtattcc catctgctat atgggatatt tcatacggct attttgaggt 53280 tataaaagat aaagtgttcc cagtgcctgg ccttgataaa ggtaactctg catatgaatt 53340 aattctgatc cctgacagaa catttatagc aaaaagtgcc cattgttgat aagttgtttt 53400 cttctaatga tagaactact tcagtatcaa ctttaattgc caagaatttc atgcctccct 53460 ctctatcctt tgcttgggaa aactgtgaaa gagtttaaat tctggcttct atgcttaatt 53520 aagaaagtag cctcagatgt ttaaaagcat aaaatattag atctacacca tgaggttctc 53580 attagagttc aaatagttac ttgttcattg attggagaaa tatttttcaa tgtcaatttg 53640 gatggagcat tttgaggagg aaagtcttga atatttaatt ttccttagca tctattttat 53700 tttcaggttc agatctggga aaaaaacaag agactcaatg gagacanaag aaaatcccaa 53760 ggttctaata actgcattct gaaaaaatat ctaccccatt tggtgaagtg aaaaacacaa 53820 aaataagacc ctgtggagaa attcgttgtt cccactgaaa tggactgact gtaacgattg 53880 acaccaaaat gaaccttgct atcaagaaat gctcgtcata cagtaaactc tggatgattc 53940 ttccagataa tgtccttgct ttacaaacca accatttcta gagagtctcc ttactcatta 54000 attcaatgaa atggattggt aagatgtctt gaaaacatgt tagtcaagga ctggtaaaat 54060 acatataaag attaacactc atttnccaat catacaaata ctatccaaat aaaaataaca 54120 tcattgtatt aacgcaaata ttaggtgaca acnaatgtgt gtgtatgtgt gtgtgtttgt 54180 acatgtggaa gtgaaccagc acagtcaaaa ttatagtagt ttctgaagtg aaccaaatga 54240 ttatatgcag nattcctatc cagaaaacct tccacactcc tttgagaggg agtgatcact 54300 gttagaggaa aaaacaaacc actttttacc ctgtactgtc acactcaacc cacaatactt 54360 ctgtgaccag atgtggtggg gggcttctca tacaccaagt aattctccag cagataccaa 54420 tggggtgttc tctaatagaa ttaagctctg accctatctg cggggagata gtgtcagatc 54480 ccacaggttg tgtgctctgt ccctcttcag atgccattcn aacatccaag ccacacgcac 54540 ctctgaccta 54550 

What is claimed is:
 1. An isolated OCTN1 polynucleotide, wherein the OCTN1 polynucleotide has a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:7; fragments of SEQ ID NO:7, where in the fragments are at least twenty nucleotides in length and contain a sequence corresponding to the L503F residue of SEQ ID NO:7; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:39; and SEQ ID NO:40.
 2. The OCTN1 polynucleotide of claim 1, further comprising a polynucleotide vector in which the OCTN1 polynucleotide is situated.
 3. An article of manufacture, comprising: (a) a polynucleotide hybridisation probe that is homologous to a OCTN 1 polynucleotide; and specifically binds under stringent hybridization conditions to the OCTN1 polynucleotide, wherein the OCTN1 polynucleotide has a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:1; fragments of SEQ ID NO:1, where in the fragments are at least twenty nucleotides in length; SEQ ID NO:36; fragments of SEQ ID NO:36, where in the fragments are at least twenty nucleotides in length; SEQ ID NO:37; fragments of SEQ ID NO:37, where in the fragments are at least twenty nucleotides in length; SEQ ID NO:7; fragments of SEQ ID NO:7, where in the fragments are at least twenty nucleotides in length and contain a sequence corresponding to the L503F residue of SEQ ID NO:7; SEQ ID NO:9; SEQ ID NO:10; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:39; and SEQ ID NO:40; and (b) a set of instruction regarding the use of the polynucleotide hybridization probe in the diagnosis of Inflammatory Bowel Disease (IBD).
 4. An isolated OCTN2 polynucleotide, wherein the OCTN2 polynucleotide has a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:8; fragments of SEQ ID NO:8, where in the fragments are at least twenty nucleotides in length and contain a sequence corresponding to the G-207C residue of SEQ ID NO:8; SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; and SEQ ID NO:35.
 5. The OCTN2 polynucleotide of claim 5, further comprising a polynucleotide vector in which the OCTN2 polynucleotide is situated.
 6. An article of manufacture, comprising: (a) a polynucleotide hybridization probe that is homologous to an OCTN2 polynucleotide and specifically binds under stringent hybridization conditions to the OCTN2 polynucleotide, OCTN2 polynucleotide has a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:3; fragments of SEQ ID NO:3, where in the fragments are at least twenty nucleotides in length; SEQ ID NO:23; fragments of SEQ ID NO:23, where in the fragments are at least twenty nucleotides in length; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:8; fragments of SEQ ID NO:8, where in the fragments are at least twenty nucleotides in length and contain a sequence corresponding to the G-207C residue of SEQ ID NO:8; SEQ ID NO:5; SEQ ID NO:6; SEQ ID NO:11; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:29; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; and SEQ ID NO:35; and (b) a set of instruction regarding the use of the polynucleotide hybridization probe in the diagnosis of Inflammatory Bowel Disease (IBD).
 7. A method for determining a susceptibility to Inflammatory Bowel Disease (IBD) in a mammal, comprising: (a) obtaining a biological sample from a mammal; (b) contacting the biological sample with polynucleotide probe that selectively binds an OCTN1 polynucleotide or an OCTN2 polynucleotide; and (c) determining the expression of the OCTN1 polynucleotide or the OCTN2 polynucleotide as a measure of susceptibility of the mammal to Inflammatory Bowel Disease.
 8. The method of claim 7, wherein the expression of the OCTN1 polynucleotide or the OCTN2 polynucleotide in the biological sample is reduced in mammals having a susceptibility to Inflammatory Bowel Disease as compared with mammals that are not susceptibel to Inflammatory Bowel Disease.
 9. The method of claim 7, wherein the biological sample is selected from the group consisting of gastrointestinal tract tissue and immune system tissue.
 10. The method of claim 7, wherein the biological sample is selected from inflamed tissue.
 11. The method of claim 7, wherein the mammal is human.
 12. The method of claim 7, wherein the Inflammatory Bowel Disease is selected from the group consisting of Crohn's disease (CD), indeterminate colitis (IC) and ulcerative colitis (UC).
 13. The method of claim 7, wherein the determination of the expression is by Northern analysis.
 14. The method of claim 7, wherein the determination of the expression is by polymerase chain reaction.
 15. The method of claim 7, wherein the expression of both the OCTN1 polynucleotide and the OCTN2 polynucleotide in the biological sample is determined.
 16. The method of claim 7, wherein the basal transcription of the OCTN2 gene is downregulated.
 17. The method of claim 7, wherein the transcription of the OCTN2 gene induced either by heat shock or by arachidonic acid is downregulated.
 18. The method of claim 7, wherein both the basal transcription of the OCTN2 gene and the transcription of the OCTN2 gene induced either by heat shock or by arachidonic acid is downregulated.
 19. A method for determining a susceptibility to inflammatory bowel disease (IBD), in a human, comprising: (a) determining the polynucleotide sequence of the OCTN1 gene or the OCTN2 gene for a human; and (a) determining that the polynucleotide sequence of the OCTN1 gene or the OCTN2 gene for the human contains a polymorphism that results in reduced expression of OCTN1 or OCTN2 in the human.
 20. The method of claim 19, wherein the polynucleotide sequences of both the OCTN1 gene and the OCTN2 gene are determined for the human.
 21. The method of claim 19, wherein the polynucleotide sequence of the OCTN1 gene contains at least one L503F polymorphism.
 22. The method of claim 19, wherein the polynucleotide sequence of the OCTN1 gene significantly reduces the ability of the encoded OCTN1 polypeptide to transport carnitine.
 23. The method of claim 19, wherein the polynucleotide sequence of the OCTN2 gene contains at least one polymorphism selected from the group consisting of G-207C, 410 and TA.
 24. The method of claim 19, wherein the polynucleotide sequence of the OCTN2 gene contains at least one polymorphism in the OCTN2 promoter region.
 25. The method of claim 19, wherein the polymorphism alters the binding of heat shock transcription factor 1 (HSF1) to the OCTN2 promoter.
 26. The method of claim 19, wherein the polymorphism of the OCTN2 gene downregulates basal transcription.
 27. The method of claim 19, wherein the polymorphism of the OCTN2 gene downregulates transcription induced either by heat shock or by arachidonic acid.
 28. The method of claim 19, wherein the polymorphism in the OCTN2 gene downregulates both basal transcription and transcription induced either by heat shock or by arachidonic acid.
 29. A method for identifying an anti-inflammatory agent, comprising: (a) forming a complex between the heat shock factor 1 (HSF1) protein and a polynucleotide comprising an OCTN2 promoter region; (b) contacting the complex with an agent suspected of dissociating the complex; and (c) detecting the dissociation of the complex, wherein the dissociation of the complex identifies the agent as being an agent that is an anti-inflammatory agent.
 30. A method for detecting a nucleotide polymorphism in a mammalian OCTN1 gene or a mammalian OCTN2 gene associated with an Inflammatory Bowel Disease, which method comprises: detecting a variation in a sequence of a gene encoding OCTN1 or OCTN2 obtained from a mammal diagnosed with or suspected of having Inflammatory Bowel Disease.
 31. The method of claim 30, wherein the mammal is human.
 32. The method of claim 30, wherein the expression of the OCTN1 gene is significantly downregulated in inflamed tissue in the mammal.
 33. The method of claim 30, wherein the expression of the OCTN2 gene is significantly downregulated in inflamed tissue in the mammal.
 34. A method for identifying a compound for treating an Inflammatory Bowel Disease, which method comprises: (a) contacting a test compound with a system for measuring carnitine transport activity, which system comprises an OCTN1 or OCTN2 polypeptide or a functional fragment of an OCTN1 or OCTN2 polypeptide, and a substrate for measuring carnitine transport by the system; and (b) detecting an increase in the carnitine transport activity of the in the presence of the test compound compared to the carnitine transport activity in the absence of the test compound.
 35. The method of claim 34, wherein the test compound is a small molecule.
 36. The method of claim 34, wherein the test compound is an intracellular factor that binds to the OCTN1 or the OCTN2 polypeptide.
 37. The method of claim 34, wherein the test compound is an extracellular factor that binds to the OCTN1 or the OCTN2 polypeptide.
 38. The method of claim 34, wherein the substrate for measuring carnitine transport is selected from the group consisting of consisting of carnitine, tetraethyl ammonium (TEA) and other compounds transported by the OCTN1 or the OCTN2 transporters.
 39. The method of claim 34, wherein the OCTN1 polypeptide is encoded by a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:7 and functional fragments thereof containing a sequence corresponding to the L503F residue of SEQ ID NO:7.
 40. The method of claim 34, wherein the OCTN2 polypeptide is encoded by a nucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:8; and functional fragments thereof containing a sequence corresponding to the G-207C residue of SEQ ID NO:8.
 41. A method for identifying a compound for modulating carnitine transport, which method comprises: (a) contacting a test compound with a system for measuring carnitine transport activity, which system comprises an OCTN1 or an OCTN2 polypeptide or a functional fragment of an OCTN1 or an OCTN2 polypeptide, and a substrate for measuring carnitine transport by the system; and (b) detecting a modulation in the carnitine transport activity of the in the presence of the test compound compared to the carnitine transport activity in the absence of the test compound.
 42. The method of claim 41, wherein the compound enhances the transporter function of OCTN1.
 43. The method of claim 41, wherein the compound reduces or blocks the transporter function of OCTN1.
 44. The method of claim 41, wherein the compound enhances the transporter function of OCTN2.
 45. The method of claim 41, wherein the compound reduces or blocks the transporter function of OCTN2.
 46. A method for identifying a compound for treating an Inflammatory Bowel Disease, which method comprises: (a) obtaining a transgenic mammal or a muatnt mammal, which mamal has a nucleotide polymorphism in an OCTN1 gene or the OCTN2 gene, wherein the polymorphism in the OCTN1 gene or the OCTN2 gene reduces the tissue expression of the OCTN1 gene or the OCTN2 gene; (b) contacting the mammal with a test compound; and (b) detecting an improvement in a condition of the mammal in response to the test compound, wherein the condition is a symptom of an Inflammatory Bowel Disease.
 47. The method of claim 46, wherein the mamal has a mutation in both the OCTN1 gene and the OCTN2 gene.
 48. The method of claim 46, wherein the Inflammatory Bowel Disease is selected from the group consisting of Crohn's disease (CD), indeterminate colitis (IC) and ulcerative colitis (UC). 